WO2010061846A1 - Orally rapidly disintegrating tablet, and process for producing same - Google Patents
Orally rapidly disintegrating tablet, and process for producing same Download PDFInfo
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- WO2010061846A1 WO2010061846A1 PCT/JP2009/069850 JP2009069850W WO2010061846A1 WO 2010061846 A1 WO2010061846 A1 WO 2010061846A1 JP 2009069850 W JP2009069850 W JP 2009069850W WO 2010061846 A1 WO2010061846 A1 WO 2010061846A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention is a novel intraoral speed that can be manufactured with ordinary tablet manufacturing equipment, has a practical formulation strength in each process such as manufacturing, distribution, and dispensing, and exhibits rapid disintegration in the oral cavity.
- the present invention relates to a disintegrating tablet and a method for producing the same.
- intraoral rapidly disintegrating tablets have been developed and marketed, such as preparations produced using a freeze-drying method, but in recent years, from the viewpoint of production costs, special prescription ingredients and Research and development on intraoral rapidly disintegrating preparations that can be prepared with ordinary equipment without using production equipment has become the mainstream.
- intraoral rapidly disintegrating tablets do not break during the manufacturing, distribution and dispensing processes, and operations such as taking out from PTP (Press Through Package). Physical strength (hardness) is required. From the standpoint of ingestion, the tablets are often blended with a sugar alcohol having a refreshing feeling (mannitol, erythritol, etc.) as an excipient.
- mannitol erythritol, etc.
- Patent Document 1 discloses an intraorally rapidly disintegrating tablet obtained by compression molding a mixture comprising a sugar alcohol or saccharide having an average particle size of 30 ⁇ m or less, an active ingredient and a disintegrant. Is disclosed.
- pulverized mannitol is used as a prescription ingredient, it is easy to induce tableting troubles such as adhesion to a pestle and mortar, and there is a problem that the fluidity of the tableting mixture is lowered.
- Patent Document 2 discloses an intraoral rapid disintegration obtained by compression molding a mixture of sugar alcohol or saccharide having an average particle size of 30 to 300 ⁇ m, an active ingredient, a disintegrant and celluloses.
- Patent Document 3 discloses compression molding of a mixture comprising an active ingredient, crystalline cellulose, lactose, agar powder and low-substituted hydroxypropylcellulose or hydroxypropyl starch.
- An intraorally rapidly disintegrating tablet obtained by the method is disclosed. Since these tablets have a relatively large amount of water-insoluble components in the preparation, they have a drawback such as a bad touch when taken.
- Patent Document 4 JP 2000-44490 A discloses a fast disintegrating tablet containing a C-type methacrylic acid copolymer listed in the United States Pharmacopeia (USP / NF) as a disintegrant or a disintegration aid.
- USP / NF United States Pharmacopeia
- this tablet is basically produced by a direct tableting method, and the polymer that can be used is also limited to C-type methacrylic acid copolymer (registered trademark: Eudragit L100-55 or L30D-55). .
- Patent Document 5 Japanese Patent Application Laid-Open No. 2004-315483 (Patent Document 5) and Japanese Patent Application Laid-Open No. 2006-199632 (Patent Document 6), a granulated product made of a mixture containing sugar or sugar alcohol and a water-insoluble hydrophilic component is compression-molded.
- An intraorally rapidly disintegrating tablet obtained by the method is disclosed. These tablets include trehalose, lactose or mannitol (or mixtures thereof) as excipients, starch as a water-insoluble hydrophilic component, starch-containing flour, fine silica, hydroxypropyl starch or crospovidone (or their Mixture).
- Patent Document 5 describes test results showing that tablet hardness decreases to about 1 ⁇ 2 under humidified storage conditions (25 ° C./75% RH).
- Non-patent Document 1 The 27th Annual Meeting of the PLCM Symposium (Non-patent Document 1) includes a water-insoluble substance in a mixture of mannitol and crospovidone as an excipient suitable for the production of an orally rapidly disintegrating tablet by direct compression.
- a granule obtained by spray granulation of Kollicoat SR30D an aqueous dispersion of vinyl acetate is disclosed.
- this document does not describe water-insoluble substances other than Kollicoat SR30D.
- the formulation characteristics in the oral cavity
- the material has the property that the disintegration property and hardness of the material can be substantially maintained.
- the rapidly disintegrating tablet in the oral cavity can be manufactured with normal tablet manufacturing equipment, and the characteristics of the formulation (tablet hardness and oral cavity) in each process such as manufacturing, distribution and dispensing. It is desired to develop a preparation that can substantially maintain the rapid disintegration property.
- the inventors of the present invention have prepared excipients with good wettability (wetability) in water as a prescription component in producing an orally rapidly disintegrating tablet.
- Sugar alcohol, etc. and water-insoluble polymers that have good moldability and do not reduce the wettability of the excipient in water.
- a rapidly disintegrating tablet in the oral cavity is obtained that has sufficient hardness and is difficult to cause changes in characteristics due to factors such as humidity (decrease in tablet hardness and delay of rapid disintegration time in the oral cavity).
- the present invention has been completed.
- the present invention is: (1) (a) active ingredient; (b) excipient with good wettability in water; (c) water with good moldability and which does not substantially reduce the wettability of the excipient into water.
- An insoluble polymer and (d) an intraoral rapidly disintegrating tablet obtained by compression molding a mixture comprising a disintegrant and having an oral disintegration time of 60 seconds or less;
- the excipient having good wettability with water is one or more sugar alcohols selected from the group consisting of mannitol, erythritol and xylitol, and the moldability is good and the excipient has good wettability with water.
- a water-insoluble polymer that does not substantially reduce water is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, ethylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer S, and aminomethacrylate copolymer
- the intraorally rapidly disintegrating tablet according to (1) which is the above water-insoluble polymer; (3) 30 to 95 parts by weight of an excipient having good water wettability with respect to 100 parts by weight of the tablet, and substantially good wettability of the excipient with good moldability
- the intraoral rapidly disintegrating tablet according to (3) wherein the tablet strength is 100 to 300 N / cm 2 ; (5)
- the active ingredient is nicergoline, imidapril hydrochloride, bisoprolol fumarate or taltilelin hydrate, and the amount of the active ingredient is 1 to 10 parts by weight with respect to 100 parts by weight of the tablet.
- Oral disintegrating tablets (17) The intraoral rapidly disintegrating tablet according to (12), wherein the active ingredient is allopurinol or avanafil, and the amount of the active ingredient is 10 to 50 parts by weight with respect to 100 parts by weight of the tablet; (18) (a) an active ingredient selected from the group consisting of nicergoline, imidapril hydrochloride, bisoprolol fumarate, tartyreline hydrate, allopurinol and avanafil; (b) one or more selected from the group consisting of mannitol, erythritol and xylitol Excipient; (c) one or more water-insolubles selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, ethylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer S and aminomethacrylate copolymer Polymer: (d)
- the active ingredient is nicergoline, imidapril hydrochloride, bisoprolol fumarate, taltyreline hydrate, allopurinol or avanafil, and the excipient with good wettability to water is mannitol, erythritol or xylitol, and the moldability is good
- the water-insoluble polymer that does not substantially reduce the wettability of the excipient in water is hydroxypropylmethylcellulose acetate succinate, ethylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer S and One or more water-insoluble polymers selected from the group consisting of amino methacrylate copolymers, and the disintegrant is carboxymethylcellulose calcium, carboxymethylcellulose,
- the active ingredient used in the present invention is not particularly limited as long as it is a drug that can be administered orally, but typical active ingredients include, for example, vitamins (vitamin A, vitamin B 1 , vitamin B 6). , Vitamin C, vitamin D, vitamin E, etc.), antipyretic analgesic / anti-inflammatory agents (aspirin, etenzamide, acetaminophen, ibuprofen, etc.), antipsychotics (chlorpromazine, reserpine, etc.), central nervous system drugs (tartilelin hydrate, etc.) , Antidepressants (such as imipramine), hypnotic sedatives (such as diazepam, nitrazepam, quazepam), antispasmodic drugs (such as scopolamine hydrobromide), cerebral metabolism improving drugs (such as meclofenixate hydrochloride), cerebral circulation improving drugs (such as Pinbocetin, nicergoline, etc.), antiepileptic drugs (pheny
- the amount of the active ingredient to be used is not particularly limited and varies depending on the type of the active ingredient. Generally, for example, 0.1 to 70 parts by weight, preferably 100 parts by weight, based on the tablet. May be 0.5 to 50 parts by weight, more preferably 1 to 30 parts by weight. More specifically, the blending amount of each active ingredient in the tablet is preferably determined so that a therapeutically effective amount is contained in one tablet according to its usage and dosage. For example, when the active ingredient is imidapril hydrochloride, bisoprolol fumarate, nicergoline or tartilerin hydrate, the amount of the active ingredient used is, for example, 0.1 to 70 parts by weight, preferably 0 to 100 parts by weight of the tablet.
- the amount of the active ingredient used is, for example, 10 to 50 parts by weight, preferably 10 to 40 parts by weight, and more preferably 10 to 30 parts by weight with respect to 100 parts by weight of the tablet. can do.
- the “excellent wettability with water” excipient is defined as follows. That is, when the wetting time of the tablet obtained by compression molding with a tableting pressure of 1000 kg using a flat punch having a diameter of 10 mm was measured by the operation described in Experimental Example 1 below, the wetting time was When it is within 300 seconds, the excipient corresponds to an excipient having “good water wettability”.
- excipient having good water wettability as described above examples include one or more sugars or sugar alcohols selected from the group consisting of mannitol, erythritol and xylitol. Of these, mannitol is preferred.
- the average particle size of these excipients is not particularly limited, but usually 0.1 to 500 ⁇ m, preferably 0.5 to 300 ⁇ m, particularly preferably 1 to 100 ⁇ m, is used.
- the above-mentioned excipients may be blended alone, or two or more kinds of excipients may be blended in combination.
- the blending amount of the excipient can be 30 to 95 parts by weight, preferably 40 to 95 parts by weight, with respect to 100 parts by weight of the tablet.
- the “water-insoluble polymer having“ good moldability ”and“ not substantially lowering the wettability of the excipient in water ” refers to the characteristics defined in the following (1) and (2) Is a water-insoluble polymer comprising
- Granules obtained by adding 5 parts by weight of ethanol aqueous solution (80% W / W) to a mixture comprising 97 parts by weight of excipient and 3 parts by weight of water-insoluble polymer, kneading, and drying.
- a molded product having a hardness of a molding (tablet) obtained by compression molding (tablet with a diameter of 10 mm, tableting pressure: 1000 kg).
- the water-insoluble polymer corresponds to a “water-insoluble polymer having good moldability”.
- the wetting time of a tablet composed of the excipient and water-insoluble polymer prepared as described in (1) above is measured by the method described in Experimental Example 1 below, the wetting time is within 300 seconds.
- the water-insoluble polymer corresponds to a water-insoluble polymer that does not substantially reduce the wettability of the excipient in water.
- the water-insoluble polymer that has good moldability as described above and does not substantially reduce the wettability of the excipient to water is not particularly limited as long as it has such characteristics.
- Propylmethylcellulose acetate succinate eg HPMC-AS / Shin-Etsu Chemical
- ethylcellulose eg etosel / Dow Chemical
- methacrylic acid copolymer L eg Eudragit L / Rame
- methacrylic acid copolymer S eg Eudragit S / Rame
- Enteric polymers such as hydroxypropylmethylcellulose phthalate (eg HP-50 / Shin-Etsu Chemical) or carboxymethylethylcellulose (eg CMEC / Sanyo Chemical Industries), or aminomethacrylate copolymers (eg Eudragit RS or RL / R).
- hydroxypropylmethylcellulose acetate succinate or hydroxypropylmethylcellulose phthalate is preferred.
- the average particle size of these water-insoluble polymers is not particularly limited, but usually 0.1 to 500 ⁇ m, preferably 0.5 to 300 ⁇ m, particularly preferably 1 to 100 ⁇ m, is used.
- the above water-insoluble polymers may be blended alone or in combination of two or more water-insoluble polymers.
- the compounding amount of the water-insoluble polymer can be 1 to 10 parts by weight, preferably 3 to 10 parts by weight with respect to 100 parts by weight of the tablet.
- Disintegrators include, for example, carboxymethylcellulose calcium, low substituted hydroxypropylcellulose, carboxymethylcellulose, celluloses such as crosslinked sodium carboxymethylcellulose or crystalline cellulose, starches such as corn starch, partially pregelatinized starch or carboxymethyl starch sodium, crosslinked And polyvinyl pyrrolidone.
- the amount of the disintegrant to be added is usually 1 to 15 parts by weight, preferably 3 to 10 parts by weight with respect to 100 parts by weight of the tablet.
- the lubricant examples include magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid ester, talc, polyethylene glycol and the like.
- the blending amount of the lubricant can be 0.01 to 3 parts by weight, preferably 0.01 to 2 parts by weight, and more preferably 0.01 to 1 part by weight with respect to 100 parts by weight of the tablet.
- additives other than the above may be blended in an appropriate amount depending on the blending purpose, if desired.
- such components include binders, plasticizers, coating agents, anti-aggregating agents, solubilizers, sweeteners, acidulants, corrigents, pH adjusters, solubilizers, colorants, and fragrances.
- the binder include sodium alginate, gelatin, dextrin, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and the like.
- the plasticizer include triethyl citrate, glycerin fatty acid ester, polyethylene glycol and the like.
- Examples of the coating agent include ethyl cellulose and hydroxypropyl methyl cellulose.
- Examples of the aggregation inhibitor include talc and calcium stearate.
- Examples of the solubilizer include sucrose fatty acid ester, sorbitan monostearate, sodium lauryl sulfate and the like.
- Examples of the sweetener include aspartame, saccharin, dipotassium glycyrrhizinate, stevia and the like.
- Examples of acidulants (organic acids) include citric acid, malic acid, ascorbic acid, fumaric acid and the like.
- Examples of the corrigent include l-menthol, sodium chloride, acesulfame potassium, sucralose and the like.
- Examples of the pH adjuster include citrate, phosphate, carbonate, acetate and the like.
- Examples of the solubilizer include cyclodextrin, arginine, lysine, trisaminomethane and the like.
- Examples of the colorant include yellow iron sesquioxide, iron sesquioxide, and copper chlorophyllin sodium.
- Examples of the fragrance include orange oil, lemon oil, mint oil, eucalyptus oil and the like.
- the intraorally rapidly disintegrating tablet of the present invention can be produced by a conventional method in tablet production.
- i) (a) an active ingredient; (b) an excipient having good wettability in water; c) a water-insoluble polymer that has good moldability and does not substantially reduce the wettability of the excipient in water; and (d) a mixture of disintegrants (the mixture is a lubricant, binder, plasticizer, Even if it contains one or more additives selected from the group consisting of a coating agent, an anti-aggregation agent, a solubilizer, a sweetener, a sour agent, a corrigent, a pH adjuster, a solubilizing agent, a colorant and a fragrance. Good) and then ii) by compression molding the mixture obtained in i) above.
- the above components (a) to (d) and other additives can be mixed by sequentially mixing the powders of the components.
- desired ingredients for example, excipient and water-insoluble polymer, or active ingredient, excipient and water-insoluble polymer
- desired ingredients for example, excipient and water-insoluble polymer, or active ingredient, excipient and water-insoluble polymer
- the granule and the remaining ingredients Disintegrants, lubricants, sweeteners, sour additives, etc.
- the components (a) to (d) or other additives may be coated in advance by conventional means using a water-soluble or water-insoluble film-forming polymer, if necessary.
- the method of mixing each of the above components is not particularly limited, and is a double cone mixer (for example, double cone mixer / manufactured by Yashima Koki), a fluidized bed granulator (manufactured by Multiplex / Paurek, Spiral Flow). / Freund's), high-speed agitation granulator (high speed mixer / Fukae Powtec, vertical granulator / Powrec), vibrating sieve (Maldalton's vibrating sieve), etc. can be used according to conventional methods. .
- a double cone mixer for example, double cone mixer / manufactured by Yashima Koki
- a fluidized bed granulator manufactured by Multiplex / Paurek, Spiral Flow
- / Freund's high-speed agitation granulator
- high speed mixer / Fukae Powtec high speed mixer / Fukae Powtec, vertical granulator / Powrec
- vibrating sieve Mildalton's vibr
- a dry granulation method for example, a dry granulation method, a wet granulation method or the like can be used.
- desired granules can be obtained by granulating the powder mixture of the components (a) to (d) using a roller compactor, a roll granulator or the like.
- a water-insoluble polymer (c ) Solution for example, ethanol solution, ethanol / water solution
- aqueous dispersion for example, by spraying or the like
- the resulting granulated product is dried to be suitable for subsequent compression molding
- desired granules can be obtained.
- the granulated granules thus obtained are subjected to various additives (eg, disintegrants, lubricants, solubilizers, sweeteners, acidulants, corrigents, pH adjusters, solubilizers) as necessary prior to compression molding. May be mixed with one or more additives selected from the group consisting of an agent, a colorant and a fragrance.
- additives eg, disintegrants, lubricants, solubilizers, sweeteners, acidulants, corrigents, pH adjusters, solubilizers
- the compression molding of the mixture of components (a) to (d) thus obtained can be carried out using a conventional tableting machine such as a single tableting machine or a rotary tableting machine.
- the tableting pressure may be appropriately selected according to the properties (hardness and the like) of the target tablet, but is usually 10 to 5000 kg / ⁇ , preferably about 20 to 4000 kg / ⁇ , and particularly preferably about 100 to 2000 kg / ⁇ .
- the tableting pressure can be carried out.
- compression molding in order to prevent tableting troubles such as sticking, tableting of a mixture of the above components (a) to (d) and tableting of a mixture of a lubricant and a fluidizing agent are performed.
- An alternating method Japanese Patent Laid-Open No. 10-298061
- a method of compression molding while spraying lubricant powder onto a tableting punch Japanese Patent Publication No. 48-20103
- the intraoral rapidly disintegrating tablet of the present invention is, for example, A) Water-insoluble in a mixture of the active ingredient (a) and an excipient (b) having good wettability to water, which has good moldability and does not substantially reduce the wettability of the excipient to water.
- Granulate while adding polymer (c) solution (for example, ethanol / water solution) or aqueous dispersion, and after drying the granulated product, the resulting granule and disintegrant, and other desired additions as required Or a mixture of a product (a lubricant, a sweetener, a sour agent such as an organic acid, etc.) and compression-molding the mixture, or B) an excipient having good moldability and good wettability to water
- a solution of a water-insoluble polymer (c) that has good moldability and does not substantially reduce the wettability of the excipient to water for example, an ethanol / water solution
- an aqueous dispersion is added.
- the active ingredient (a), a disintegrant, and other desired additives as required can be mixed, and the mixture can be compression-molded.
- the active ingredient or other additives may be coated with a film-forming polymer such as ethyl cellulose, if necessary.
- the shape of the intraoral rapidly disintegrating tablet of the present invention is not particularly limited, and may be various shapes such as a circle, an ellipse, a caplet type, and a donut type.
- preferable tablet hardness (hardness measured by a tablet hardness meter) varies depending on factors such as shape, size, weight, etc., but for example, a circular tablet having a diameter of 5 to 10 mm ( In the case of a weight of 100 to 300 mg), it is usually 15 N to 90 N, preferably 20 N to 90 N, more preferably 40 N to 90 N, still more preferably 50 to 90 N.
- the tablet strength (value of the ratio between tablet hardness and tablet break area) in the intraoral rapidly disintegrating tablet of the present invention is usually 100 N / cm 2 or more, preferably 110 to 300 N / cm 2 , more preferably 120. ⁇ 300 N / cm 2 .
- the disintegration time in the oral cavity of the tablet of the present invention varies depending on its shape and thickness, but is usually within 60 seconds (5 to 60 seconds), preferably 5 to 45 seconds, more preferably 5 to 35 seconds, It is preferably 5 to 30 seconds, particularly preferably within 20 seconds (5 to 20 seconds).
- tablets suitable for packaging using an automatic tablet packaging machine can be easily obtained. Such tablets are desirable for reducing or avoiding tablet breakage during the packaging operation.
- Such a tablet varies depending on factors such as the shape, size, and weight of the tablet.
- the value of the ratio of hardness to tablet weight is 0.2 N / mg or more, preferably 0.3 N / mg or more.
- Experimental example 1 300 mg of a mixture of 97 parts by weight (or 90 parts by weight) of excipient and 3 parts by weight (or 10 parts by weight) of a water-insoluble polymer (hydroxypropylmethylcellulose acetate succinate, HPMC-AS, grade; HF) is applied to a compaction analyzer (Kikusui). Tablets were obtained by compression molding with a tableting pressure of 1000 kg / ⁇ using a flat plate made by Seisakusho (diameter: 10 mm in diameter). Water wettability (wetting time) and hardness of each tablet were measured according to the following evaluation methods, respectively, and the excipients were classified into the following two groups based on the measurement results (Table 1 below). .
- a water-insoluble polymer hydroxypropylmethylcellulose acetate succinate, HPMC-AS, grade; HF
- Tablets were obtained by compression molding with a tableting pressure of 1000 kg / ⁇ using a flat plate made by Seisakusho (diameter: 10
- Group A An excipient having good wettability to water and moldability when containing a water-insoluble polymer, wherein the tablet wetting time is within 300 seconds and the tablet hardness is 3 times or more of the excipient alone.
- Group B An excipient having poor wettability to water or moldability when containing a water-insoluble polymer, wherein the tablet wetting time is 300 seconds or more, or the tablet hardness is 3 times or less of the excipient alone.
- Evaluation methods a) Water wettability of tablets (wetting time) The wettability (wetting time) of the tablet with water is determined by a known method [Chem. Pharm. Bull. 44 (1), 2121-2127 (1996)], the measurement was performed as follows.
- tissue paper 205 mm ⁇ 120 mm, Kimwipe S-200, manufactured by Nippon Paper Crecia
- One tablet was allowed to stand, and the time (wetting time) required until the entire tablet was wet was measured.
- Tablet hardness The tablet hardness was measured using a tablet hardness tester (manufactured by Schleuniger, model: 6D). The measurement was performed three times, and the average value was taken as the hardness of the tablet.
- the wettability (wetting time) and hardness of each tablet in water were measured according to the evaluation method described in Experimental Example 1. Based on the measurement results (Table 2 below), the water-insoluble polymers were classified into the following three groups.
- Group 1 A water-insoluble polymer having a tablet wetting time of 300 seconds or less, a tablet hardness of 3 times or more that of mannitol alone, and having good moldability without reducing the wettability of sugar alcohol with water.
- Group 2 Tablets containing water-insoluble polymers have a wetting time of less than 300 seconds, and tablet hardness is 3 times or less that of mannitol alone, but do not reduce the wettability of sugar alcohol to water, but have poor moldability.
- Group 3 A tablet containing a water-insoluble polymer has a wetting time of 300 seconds or more and a tablet hardness of 3 times or more that of mannitol alone. molecule.
- the water-insoluble polymer classified into Group 1 is preferable as the water-insoluble polymer applied to the orally disintegrating preparation according to the present invention.
- Example 1 (1) 80% of 5 parts by weight in a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of hydroxypropylmethylcellulose acetate succinate (grade: HF) sieved with a 22-mesh screen of Japanese Pharmacopoeia (opening: 710 ⁇ m) ( W / W) After granulation while adding an aqueous ethanol solution, the granulated granule was obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
- HF hydroxypropylmethylcellulose acetate succinate
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 84 N, disintegration time in the oral cavity: 15 seconds) is obtained in the same manner as (2) except that the tableting pressure is 1250 kg / kg. It was.
- Example 2 (1) 5 parts by weight of 80% (W / W) in a mixture of 90 parts by weight of erythritol and 10 parts by weight of hydroxypropyl methylcellulose acetate succinate (grade; HF) sieved with a 60-mesh screen of Japanese Pharmacopoeia (opening: 250 ⁇ m) W) After granulation while adding an aqueous ethanol solution, granulation granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer. (2) 283.5 parts by weight of the granulated granules (1), 15 parts by weight of crospovidone and 1.5 parts by weight of magnesium stearate were mixed to obtain granules for tableting.
- Example 3 (1) Preparation of granules 90 parts by weight of xylitol, which was pulverized using an agate mortar and then sieved with a Japanese pharmacopoeia 60 mesh sieve (opening: 250 ⁇ m), and 10 parts by weight of hydroxypropylmethylcellulose acetate succinate (grade; HF) After granulation while adding 5 parts by weight of 80% (W / W) aqueous ethanol solution to the mixture, granulation granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
- Example 4 (1) 80% of 5 parts by weight in a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of hydroxypropylmethylcellulose acetate succinate (grade; MF) sieved with a Japanese pharmacopoeia 22 mesh sieve (aperture: 710 ⁇ m) W / W) After granulation while adding an aqueous ethanol solution, the granulated granule was obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
- grade; MF hydroxypropylmethylcellulose acetate succinate
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 87 N, disintegration time in the oral cavity: 17 seconds) is obtained in the same manner as in the above (2) except that the tableting pressure is 1100 kg / kg. It was.
- Example 5 (1) 80% of 5 parts by weight in a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of hydroxypropylmethylcellulose acetate succinate (grade; LF) sieved with a Japanese pharmacopoeia 22 mesh sieve (aperture: 710 ⁇ m) W / W) After granulation while adding an aqueous ethanol solution, the granulated granule was obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
- grade; LF hydroxypropylmethylcellulose acetate succinate
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 82 N, disintegration time in the oral cavity: 22 seconds) is obtained in the same manner as (2) except that the tableting pressure is 1350 kg / kg. It was.
- Example 6 While adding 5 parts by weight of 80% (W / W) ethanol aqueous solution to a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of ethylcellulose sieved with a 22-mesh sieve (mesh size: 710 ⁇ m) After granulation, the granulated granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 80 N, disintegration time in the oral cavity: 16 seconds) is obtained in the same manner as (2) except that the tableting pressure is 1400 kg / kg. It was.
- Example 7 (1) 5 parts by weight in a mixture of 97 parts by weight of D-mannitol sieved with a Japanese pharmacopoeia 22 mesh sieve (aperture: 710 ⁇ m) and 3 parts by weight of hydroxypropyl methylcellulose phthalate (grade; HP-50) ground with an agate mortar After granulating while adding 80% (W / W) aqueous ethanol solution, granulated granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 80 N, disintegration time in the oral cavity: 17 seconds) is obtained in the same manner as in the above (2) except that the tableting pressure is 1500 kg / kg. It was.
- Example 8 (1) 80% (W / W) of 5 parts by weight in a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of aminomethacrylate copolymer (Eudragit RSPO) sieved with a 22-mesh pharmacopoeia (mesh size: 710 ⁇ m) After granulation while adding an aqueous ethanol solution, the granulated granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
- Eudragit RSPO aminomethacrylate copolymer
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 86 N, disintegration time in the oral cavity: 18 seconds) is obtained in the same manner as in the above (2) except that the tableting pressure is 1500 kg / kg. It was.
- Example 9 (1) 80% (W / W) of 5 parts by weight in a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of aminomethacrylate copolymer (Eudragit RLPO) sieved with a 22-mesh screen of Japanese Pharmacopoeia (aperture: 710 ⁇ m) After granulation while adding an aqueous ethanol solution, the granulated granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
- Eudragit RLPO aminomethacrylate copolymer
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 84 N, disintegration time in the oral cavity: 16 seconds) is obtained in the same manner as (2) except that the tableting pressure is 1250 kg / kg. It was.
- Example 10 (1) 5% by weight of 80% (W / W) in a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of methacrylic acid copolymer (Eudragit L100) sieved with a 22-mesh sieve of Japanese Pharmacopoeia (opening: 710 ⁇ m) After granulation while adding an aqueous ethanol solution, the granulated granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
- Eudragit L100 methacrylic acid copolymer
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 81 N, disintegration time in the oral cavity: 19 seconds) is obtained in the same manner as in the above (2) except that the tableting pressure is 1250 kg / kg. It was.
- Example 11 (1) 5 parts by weight of 80% (W / W) in a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of methacrylic acid copolymer (Eudragit S100) sieved with a Japanese pharmacopoeia 22 mesh sieve (aperture: 710 ⁇ m) After granulation while adding an aqueous ethanol solution, the granulated granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
- Eudragit S100 methacrylic acid copolymer
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 84 N, disintegration time in the oral cavity: 19 seconds) is obtained in the same manner as in the above (2) except that the tableting pressure is 1900 kg / kg. It was.
- Example 12 (1) 5 parts by weight of 80% (W / W) ethanol aqueous solution was added to a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of carboxymethyl ethyl cellulose sieved with a 22-mesh sieve (mesh size: 710 ⁇ m). Then, after granulation, granulated granules were obtained by drying at 50 ° C. for 2 hours in a ventilated box dryer.
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 84 N, disintegration time in the oral cavity: 19 seconds) is obtained in the same manner as in the above (2) except that the tableting pressure is 1900 kg / kg. It was.
- Example 13 (1) 1.8 parts by weight of imidapril hydrochloride and 95 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (aperture: 710 ⁇ m) were placed in a fluidized bed granulator (manufactured by Paulec, MP-01 / 03). The mixture was granulated while spraying 39.7 parts by weight of an aqueous solution of 80% (W / W) ethanol of 8% hydroxypropylmethylcellulose acetate succinate (grade; HF) at an air supply temperature of 60 ° C. over about 30 minutes. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 86 N, disintegration time in the oral cavity: 20 seconds) is obtained in the same manner as (2) except that the tableting pressure is 1400 kg / kg. It was.
- Example 14 (1) 1.8 parts by weight of imidapril hydrochloride and 95 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (aperture: 710 ⁇ m) were placed in a fluidized bed granulator (manufactured by Paulec, MP-01 / 03). The mixture was granulated while spraying 39.7 parts by weight of an 80% (W / W) ethanol aqueous solution of 8% hydroxypropylmethylcellulose acetate succinate (grade; MF) at a supply air temperature of 60 ° C. over about 30 minutes. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
- a rapidly disintegrating tablet in the oral cavity (weight: 300 mg, hardness: 87 N, disintegration time in the oral cavity: 22 seconds) is obtained in the same manner as (2) except that the tableting pressure is 1400 kg / kg. It was.
- Example 15 (1) 1.8 parts by weight of imidapril hydrochloride and 95 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (aperture: 710 ⁇ m) were placed in a fluidized bed granulator (manufactured by Paulec, MP-01 / 03). The mixture was granulated while spraying 39.7 parts by weight of an 80% (W / W) ethanol aqueous solution of 8% hydroxypropylmethylcellulose acetate succinate (grade; LF) at an air supply temperature of 60 ° C. over about 30 minutes. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
- a fluidized bed granulator manufactured by Paulec, MP-01 / 03
- the mixture was granulated while spraying 39.7 parts by weight of an 80% (W / W) ethanol aqueous solution of 8% hydroxypropylmethyl
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 80 N, disintegration time in the oral cavity: 26 seconds) is obtained in the same manner as (2) except that the tableting pressure is 1600 kg / kg. It was.
- Example 16 (1) 1.8 parts by weight of imidapril hydrochloride and 95 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (aperture: 710 ⁇ m) were placed in a fluidized bed granulator (manufactured by Paulec, MP-01 / 03). The mixture was charged and granulated while spraying 39.7 parts by weight of an 80% (W / W) ethanol aqueous solution of 8% hydroxypropylmethylcellulose phthalate (grade: HP-50) at an air supply temperature of 60 ° C. over about 30 minutes. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 84 N, disintegration time in the oral cavity: 23 seconds) is obtained in the same manner as in the above (2) except that the tableting pressure is 1400 kg / kg. It was.
- Example 17 (1) 1.8 parts by weight of imidapril hydrochloride and 95 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (aperture: 710 ⁇ m) were placed in a fluidized bed granulator (manufactured by Paulec, MP-01 / 03). The mixture was granulated while spraying 39.7 parts by weight of an 80% (W / W) ethanol aqueous solution of 8% amino methacrylate copolymer (Eudragit RSPO) at an air supply temperature of 60 ° C. over about 30 minutes. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
- a fluidized bed granulator manufactured by Paulec, MP-01 / 03
- the mixture was granulated while spraying 39.7 parts by weight of an 80% (W / W) ethanol aqueous solution of 8% amino methacrylate cop
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 82 N, disintegration time in the oral cavity: 20 seconds) is obtained in the same manner as in the above (2) except that the tableting pressure is 800 kg / kg. It was.
- Example 18 (1) 1.8 parts by weight of imidapril hydrochloride and 95 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (aperture: 710 ⁇ m) were placed in a fluidized bed granulator (manufactured by Paulec, MP-01 / 03). The mixture was granulated while spraying 39.7 parts by weight of an 80% (W / W) ethanol solution of 8% carboxymethylethylcellulose at an air supply temperature of 60 ° C. over about 30 minutes. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
- An intraoral rapidly disintegrating tablet (weight: 300 mg, hardness: 81 N, disintegration time in the oral cavity: 27 seconds) is obtained in the same manner as (2) except that the tableting pressure is 950 kg / kg. It was.
- Example 19 283.5 parts by weight of the granulated granules of Example 14 (1), 15 parts by weight of carboxymethyl cellulose and 1.5 parts by weight of magnesium stearate were mixed to obtain granules for tableting.
- a compaction analyzer manufactured by Kikusui Seisakusho, ⁇ : diameter 10 mm, tableting pressure: 800 kg / ⁇
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 80 N, disintegration time in the oral cavity: 25 seconds) is obtained in the same manner as in the above (1) except that the tableting pressure is 1400 kg / kg. It was.
- Example 20 283.5 parts by weight of granulated granules of Example 14 (1), 6 parts by weight of croscarmellose sodium and 1.5 parts by weight of magnesium stearate were mixed to obtain granules for tableting.
- a compaction analyzer manufactured by Kikusui Seisakusho, ⁇ : diameter 10 mm, tableting pressure: 800 kg / ⁇
- a fast disintegrating tablet in the oral cavity (weight: 291 mg, hardness: 81 N, disintegration time in the oral cavity: 23 seconds) is obtained in the same manner as (1) except that the tableting pressure is 1450 kg / kg. It was.
- Example 21 283.5 parts by weight of granulated granules of Example 14 (1), 15 parts by weight of carmellose calcium and 1.5 parts by weight of magnesium stearate were mixed to obtain granules for tableting.
- a compaction analyzer manufactured by Kikusui Seisakusho, ⁇ : diameter 10 mm, tableting pressure: 800 kg / ⁇
- a rapidly disintegrating tablet in the oral cavity (weight: 300 mg, hardness: 83 N, disintegration time in the oral cavity: 33 seconds) is obtained in the same manner as (1) except that the tableting pressure is 1450 kg / kg. It was.
- Example 22 283.5 parts by weight of granulated granules of Example 14 (1), 9 parts by weight of sodium carboxymethyl starch and 1.5 parts by weight of magnesium stearate were mixed to obtain granules for tableting.
- a compaction analyzer Karl Fischer, ⁇ : diameter 10 mm, tableting pressure: 850 kg / ⁇ ⁇
- a rapidly disintegrating tablet in the oral cavity (weight: 294 mg, hardness: 81 N, disintegration time in the oral cavity: 35 seconds) is obtained in the same manner as in the above (1) except that the tableting pressure is 1500 kg / kg. It was.
- Example 23 (1) Fluidized bed granulator (manufactured by Paulek, MP-01 / 03) was added 1.8 parts by weight of bisoprolol fumarate and 95 parts by weight of D-mannitol sieved with Japanese Pharmacopoeia 22 mesh sieve (mesh size: 710 ⁇ m). Then, 39.7 parts by weight of an 8% hydroxypropylmethylcellulose acetate succinate (grade; HF) 80% (W / W) ethanol aqueous solution was sprayed over about 30 minutes at an air supply temperature of 60 ° C. and granulated. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
- HF 8% hydroxypropylmethylcellulose acetate succinate
- W / W 80%
- An intraoral rapidly disintegrating tablet (weight: 300 mg, hardness: 83 N, disintegration time in the oral cavity: 24 seconds) is obtained in the same manner as in the above (2) except that the tableting pressure is 1400 kg / kg. It was.
- Example 24 Fluidized bed granulator comprising 2 parts by weight of bisoprolol fumarate, 88 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (mesh opening: 710 ⁇ m) and 10 parts by weight of methacrylic acid copolymer L (Eudragit L) (Powrec, MP-01 / 03), granulated while spraying 54.1 parts by weight of purified water over a period of about 25 minutes at an air supply temperature of 60 ° C, and then the temperature of the granulated product is 40 ° C or higher By drying to the end, granulated granules were obtained.
- An intraoral quick disintegrating tablet (weight: 330 mg, hardness: 80 N, disintegration time in the oral cavity: 27 seconds) is obtained in the same manner as (2) except that the tableting pressure is 1800 kg / kg. It was.
- Example 25 (1) 97 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (aperture: 710 ⁇ m) was charged into a fluidized bed granulator (manufactured by Pauleck, MP-01 / 03) at an air supply temperature of 60 ° C. After granulation while spraying 37.5 parts by weight of 8% hydroxypropylmethylcellulose acetate succinate (grade; HF) 80% (W / W) ethanol aqueous solution over about 30 minutes, the temperature of the granulated product is 40 ° C. By drying to the above, granulated granules were obtained.
- a Japanese Pharmacopoeia 22 mesh sieve aperture: 710 ⁇ m
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 85 N, disintegration time in the oral cavity: 20 seconds) is obtained in the same manner as (2) except that the tableting pressure is 1400 kg / kg. It was.
- Example 26 (1) High-speed agitation granulation of 2 parts by weight of talcylerin hydrate, 88 parts by weight of D-mannitol and 10 parts by weight of methacrylic acid copolymer S (Eudragit S) sieved with a Japanese Pharmacopoeia 22 mesh sieve (mesh opening: 710 ⁇ m) It was charged in an apparatus (Fukae Pautech, ultra-compact high-speed mixer) and premixed for 1 minute. After granulating for about 3 minutes while adding 9.3 parts by weight of purified water to the mixture, the granulated product was dried at 50 ° C. for 2 hours in a vented box dryer to obtain granulated granules.
- methacrylic acid copolymer S Eudragit S
- An intraoral rapidly disintegrating tablet (weight: 300 mg, hardness: 82 N, disintegration time in the oral cavity: 18 seconds) is obtained in the same manner as in the above (2) except that the tableting pressure is 1250 kg / kg. It was.
- Example 27 35 parts by weight of allopurinol and 62 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (aperture: 710 ⁇ m) were charged into a fluidized bed granulator (manufactured by Pauleck, MP-01 / 03). After granulation while spraying 39.7 parts by weight of 80% (W / W) aqueous ethanol solution of 8% hydroxypropylmethylcellulose acetate succinate (grade; HF) at an air temperature of 60 ° C. over about 15 minutes, the granulated product Granules were obtained by drying until the temperature became 40 ° C. or higher.
- An intraoral quick disintegrating tablet (weight: 300 mg, hardness: 85 N, disintegration time in the oral cavity: 23 seconds) is obtained in the same manner as in the above (2) except that the tableting pressure is 900 kg / kg. It was.
- Example 28 (1) A fluidized bed granulator (Powrec, MP-01 / 03) containing 34.5 parts by weight of avanafil and 61.9 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (mesh size: 710 ⁇ m) And granulated while spraying a liquid in which 3.6 parts by weight of hydroxypropylmethylcellulose acetate succinate (grade; HF) is dispersed in 53.1 parts by weight of purified water at an air supply temperature of 50 ° C. over about 25 minutes. did. The active ingredient granule was obtained by drying until the temperature of the granulated product reached 37 ° C or higher.
- the hardness and disintegration time in the oral cavity of the tablet after storing the above tablet at 25 ° C./75% RH for 1 month were measured. As a result, the hardness was 42 N and the disintegration time in the oral cavity was 26 seconds.
- Example 29 290 parts by weight of the main drug granules of Example 28 (1), 46 parts by weight of fumaric acid granules of Example 28 (2), 3.5 parts by weight of crospovidone, 3.5 parts by weight of aspartame and 7 parts by weight of magnesium stearate
- granules for tableting were obtained.
- compression molding is carried out with a rotary tableting machine (manufactured by Kikusui Seisakusho, COLLECT 12HUK, punch: diameter 10 mm, tableting pressure: 600 kg / ⁇ ) by using the granules for tableting.
- a rapidly disintegrating tablet (hardness: 52 N, disintegration time in the oral cavity: 25 seconds) was obtained.
- the hardness and disintegration time in the oral cavity of the tablet after storing the above tablet at 25 ° C./75% RH for 1 month were measured. As a result, the hardness was 46 N and the disintegration time in the oral cavity was 26 seconds.
- Example 30 (1) 36.2 parts by weight of avanafil and 60 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (mesh size: 710 ⁇ m) were charged into a fluidized bed granulator (MP-01 / 03, manufactured by Paulek). At a supply temperature of 50 ° C., granulation was carried out while spraying a solution in which 3.8 parts by weight of hydroxypropylmethylcellulose acetate succinate (grade; HF) was dispersed in 55.7 parts by weight of purified water over about 25 minutes. The active ingredient granule was obtained by drying until the temperature of the granulated product reached 37 ° C or higher.
- MP-01 / 03 fluidized bed granulator
- the hardness and disintegration time in the oral cavity of the tablet after storing the above tablet at 25 ° C./75% RH for 1 month were measured. As a result, the hardness was 40 N and the disintegration time in the oral cavity was 32 seconds.
- Example 31 (1) 3.1 parts by weight of imidapril hydrochloride and 90.9 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (mesh size: 710 ⁇ m) were added to a fluidized bed granulator (MP-01 / 03, manufactured by Paulec). And granulated while spraying 38.5 parts by weight of 80% (W / W) ethanol solution of 8% hydroxypropylmethylcellulose acetate succinate (grade; HF) at an air supply temperature of 60 ° C. over about 30 minutes did. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
- the hardness and disintegration time in the oral cavity of the tablet after storing the above tablet at 25 ° C./75% RH for 1 month were measured. As a result, the hardness was 39 N and the disintegration time in the oral cavity was 23 seconds.
- Example 32 (1) 3.1 parts by weight of imidapril hydrochloride and 92.9 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (mesh size: 710 ⁇ m) were added to a fluidized bed granulator (MP-01 / 03, manufactured by Paulec). And spraying 38.7 parts by weight of an aqueous solution of 80% (W / W) ethanol of 2.7% hydroxypropylmethylcellulose acetate succinate (grade; HF) at an air supply temperature of 50 ° C. over about 15 minutes. Granulated. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
- the hardness and disintegration time in the oral cavity of the tablet after storing the above tablet at 25 ° C./75% RH for 1 month were measured. As a result, the hardness was 41 N and the disintegration time in the oral cavity was 13 seconds.
- Example 33 (1) 3.1 parts by weight of imidapril hydrochloride and 90.9 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (mesh size: 710 ⁇ m) were added to a fluidized bed granulator (MP-01 / 03, manufactured by Paulec). And granulated while spraying 38.5 parts by weight of 80% (W / W) ethanol aqueous solution of 8% ethyl cellulose over about 15 minutes at an air supply temperature of 50 ° C. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
- the hardness and disintegration time in the oral cavity of the tablet after storing the above tablet at 25 ° C./75% RH for 1 month were measured. As a result, the hardness was 36N and the disintegration time in the oral cavity was 22 seconds.
- Example 34 (1) 3.1 parts by weight of imidapril hydrochloride and 90.9 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (mesh size: 710 ⁇ m) were added to a fluidized bed granulator (MP-01 / 03, manufactured by Paulec). And granulated while spraying 38.7 parts by weight of an 80% (W / W) ethanol aqueous solution of 8% ethylcellulose over about 15 minutes at an air supply temperature of 50 ° C. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
- the hardness and disintegration time in the oral cavity of the tablet after storing the above tablet at 25 ° C./75% RH for 1 month were measured. As a result, the hardness was 50 N and the disintegration time in the oral cavity was 20 seconds.
- Comparative Example 1 (1) 5 parts by weight of 80% (W / W) in a mixture of 97 parts by weight of sorbitol and 3 parts by weight of hydroxypropylmethylcellulose acetate succinate (grade; HF) sieved with a 60-mesh screen (mesh size: 250 ⁇ m) W) After granulation while adding an aqueous ethanol solution, the granulated product was dried at 50 ° C. for 2 hours in a vented box dryer to obtain granulated granules. (2) 283.5 parts by weight of the granulated granules (1), 15 parts by weight of crospovidone and 1.5 parts by weight of magnesium stearate were mixed to prepare granules for tableting.
- tablets were obtained by compression molding with a compaction analyzer (manufactured by Kikusui Seisakusho, ⁇ : diameter 10 mm, tableting pressure: 200 kg / ⁇ ) to give 300 mg per tablet (hardness: 57N, disintegration time in the oral cavity: 129 seconds).
- Comparative Example 2 (1) Mixing in a weight ratio of 97 parts by weight of refined white sugar and 3 parts by weight of hydroxypropylmethylcellulose acetate succinate (grade; HF), which was pulverized in an agate mortar and then passed through a 60-mesh pharmacopoeia (mesh size: 250 ⁇ m). Finally, 5 parts by weight of 80% (W / W) ethanol aqueous solution was added and granulated, and then dried at 50 ° C. for 2 hours in a vented box dryer to obtain granulated granules.
- HF hydroxypropylmethylcellulose acetate succinate
- Comparative Example 3 (1) 5 parts by weight in a mixed powder having a weight ratio of 97 parts by weight of D-mannitol and 3 parts by weight of hydroxypropylmethylcellulose (grade: TC-5EW) sieved with a 22-mesh screen (mesh size: 710 ⁇ m) After granulation while adding an 80% (W / W) aqueous ethanol solution, the granulated product was dried at 50 ° C. for 2 hours in a vented box dryer to obtain granulated granules. (2) 283.5 parts by weight of the granulated granules (1), 15 parts by weight of crospovidone and 1.5 parts by weight of magnesium stearate were mixed to prepare granules for tableting.
- tablets were obtained by compression molding with a compaction analyzer (manufactured by Kikusui Seisakusho, cocoon: diameter 10 mm, tableting pressure: 900 kg / ⁇ ) to give 300 mg per tablet (hardness: 52N, disintegration time in the oral cavity: 105 seconds).
- a compaction analyzer manufactured by Kikusui Seisakusho, cocoon: diameter 10 mm, tableting pressure: 900 kg / ⁇
- Comparative Example 4 (1) 5% by weight of 80% (W) in a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of hydroxypropylcellulose (grade: HPC-SL) sieved with a 22-mesh sieve (mesh size: 710 ⁇ m) / W) After granulation while adding an aqueous ethanol solution, granulation granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer. (2) 283.5 parts by weight of the granulated granules of (1), 15 parts by weight of crospovidone and 1.5 parts by weight of magnesium stearate were mixed to prepare granules for tableting.
- Tablets were obtained by using the granules for tableting by compression molding with a compaction analyzer (manufactured by Kikusui Seisakusho, cocoon: diameter 10 mm, tableting pressure: 850 kg / ⁇ ⁇ ) so as to be 300 mg per tablet (hardness: 52N, disintegration time in the oral cavity: 37 seconds).
- a compaction analyzer manufactured by Kikusui Seisakusho, cocoon: diameter 10 mm, tableting pressure: 850 kg / ⁇ ⁇
- a tablet (weight: 300 mg, hardness: 81 N, disintegration time in the oral cavity: 46 seconds) was obtained in the same manner as (2) except that the tableting pressure was 1350 kg / kg.
- Comparative Example 5 (1) 5 parts by weight of 80% (W / W) ethanol aqueous solution was added to a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of corn starch sieved with a Japanese pharmacopoeia 22 mesh sieve (aperture: 710 ⁇ m). Then, after granulation, granulated granules were obtained by drying at 50 ° C. for 2 hours in a ventilated box dryer. (2) 283.5 parts by weight of the granulated granules (1), 15 parts by weight of crospovidone and 1.5 parts by weight of magnesium stearate were mixed to prepare granules for tableting.
- Tablets were obtained by using the granules for tableting and compression-molding with a compaction analyzer (manufactured by Kikusui Seisakusho, cocoon: diameter 10 mm, tableting pressure: 2000 kg / ⁇ ) to give 300 mg per tablet (hardness: 57N, disintegration time in the oral cavity: 15 seconds). On the other hand, even when the tableting pressure was increased to 2000 kg / kg, tablets having a tablet hardness of 80 N or more could not be prepared.
- a compaction analyzer manufactured by Kikusui Seisakusho, cocoon: diameter 10 mm, tableting pressure: 2000 kg / ⁇
- Comparative Example 6 (1) 5 parts by weight of 80% (W / W) ethanol aqueous solution was added to a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of crospovidone sieved with a 22-mesh pharmacopoeia (mesh size: 710 ⁇ m). After granulation, the granulated product was dried at 50 ° C. for 2 hours in a vented box dryer to obtain granulated granules. (2) 283.5 parts by weight of the granulated granules (1), 15 parts by weight of crospovidone and 1.5 parts by weight of magnesium stearate were mixed to prepare granules for tableting.
- tablets were obtained by compression molding with a compaction analyzer (manufactured by Kikusui Seisakusho, cocoon: diameter 10 mm, tableting pressure: 1500 kg / ⁇ ) so as to be 300 mg per tablet (hardness: 52N, disintegration time in the oral cavity: 15 seconds). On the other hand, even when the tableting pressure was increased to 2000 kg / kg, tablets with a tablet hardness of 80 N or more were not obtained.
- the intraoral rapidly disintegrating tablet of the present invention can be manufactured with a normal tablet manufacturing facility, and has a sufficient hardness with little risk of breakage in handling in each process such as manufacturing, distribution and dispensing.
- the rapidly disintegrating tablet in the oral cavity of the present invention has characteristics changes due to factors such as humidity during the operation and subsequent storage period of the automatic tablet packaging machine (decrease in tablet hardness and delay of rapid disintegration time in the oral cavity). Etc.), it is highly practical as a pharmaceutical preparation.
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Abstract
Description
(1)(a)活性成分;(b)水への濡れ性が良好な賦形剤;(c)成形性が良好で、前記賦形剤の水への濡れ性を実質的に低下させない水不溶性高分子;及び(d)崩壊剤からなる混合物を圧縮成形して得られる口腔内での崩壊時間が60秒以内である口腔内速崩壊性錠;
(2)水への濡れ性が良好な賦形剤がマンニトール、エリスリトール及びキシリトールからなる群から選ばれる1種以上の糖アルコールであり、成形性が良好で前記賦形剤の水への濡れ性を実質的に低下させない水不溶性高分子がヒドロキシプロピルメチルセルロースアセテートサクシネート、エチルセルロース、ヒドロキシプロピルメチルセルロースフタレート、カルボキシメチルエチルセルロース、メタクリル酸コポリマーL、メタクリル酸コポリマーS及びアミノメタクリレートコポリマーからなる群から選ばれる1種以上の水不溶性高分子である、前記(1)記載の口腔内速崩壊性錠;
(3)錠剤100重量部に対し、水への濡れ性が良好な賦形剤の配合量が30~95重量部、成形性が良好で前記賦形剤の水への濡れ性を実質的に低下させない水不溶性高分子の配合量が1~10重量部、かつ崩壊剤の配合量が1~15重量部である前記(1)又は(2)記載の口腔内速崩壊性錠;
(4)錠剤強度が100~300N/cm2である、前記(3)記載の口腔内速崩壊性錠;
(5)錠剤強度が110~300N/cm2である、前記(3)記載の口腔内速崩壊性錠;
(6)錠剤強度が120~300N/cm2である、前記(3)記載の口腔内速崩壊性錠;
(7)口腔内での崩壊時間が5~45秒である、前記(4)、(5)又は(6)記載の口腔内速崩壊性錠;
(8)口腔内での崩壊時間が5~30秒である、前記(4)、(5)又は(6)記載の口腔内速崩壊性錠;
(9)口腔内での崩壊時間が5~20秒である、前記(4)、(5)又は(6)記載の口腔内速崩壊性錠;
(10)硬度と錠剤重量との比の値が0.2N/mg以上である、前記(4)、(5)又は(6)記載の口腔内速崩壊性錠;
(11)硬度と錠剤重量との比の値が0.3N/mg以上である、前記(4)、(5)又は(6)記載の口腔内速崩壊性錠;
(12)活性成分がニセルゴリン、塩酸イミダプリル、フマル酸ビソプロロール、タルチレリン水和物、アロプリノール又はアバナフィルである、前記(4)、(5)又は(6)記載の口腔内速崩壊性錠;
(13)活性成分がニセルゴリン、塩酸イミダプリル、フマル酸ビソプロロール又はタルチレリン水和物であり、活性成分の配合量が、錠剤100重量部に対して0.1~70重量部である、前記(11)記載の口腔内速崩壊性錠;
(14)活性成分がニセルゴリン、塩酸イミダプリル、フマル酸ビソプロロール又はタルチレリン水和物であり、活性成分の配合量が、錠剤100重量部に対して0.5~20重量部である、前記(12)記載の口腔内速崩壊性錠;
(15)活性成分がニセルゴリン、塩酸イミダプリル、フマル酸ビソプロロール又はタルチレリン水和物であり、活性成分の配合量が、錠剤100重量部に対して1~15重量部である、前記(12)記載の口腔内速崩壊性錠;
(16)活性成分がニセルゴリン、塩酸イミダプリル、フマル酸ビソプロロール又はタルチレリン水和物であり、活性成分の配合量が、錠剤100重量部に対して1~10重量部である、前記(12)記載の口腔内速崩壊性錠;
(17)活性成分がアロプリノール又はアバナフィルであり、活性成分の配合量が、錠剤100重量部に対して10~50重量部である、前記(12)記載の口腔内速崩壊性錠;
(18)(a)ニセルゴリン、塩酸イミダプリル、フマル酸ビソプロロール、タルチレリン水和物、アロプリノール及びアバナフィルからなる群から選ばれる活性成分;(b)マンニトール、エリスリトール及びキシリトールからなる群から選ばれる1種以上の賦形剤;(c)ヒドロキシプロピルメチルセルロースアセテートサクシネート、エチルセルロース、ヒドロキシプロピルメチルセルロースフタレート、カルボキシメチルエチルセルロース、メタクリル酸コポリマーL、メタクリル酸コポリマーS及びアミノメタクリレートコポリマーからなる群から選ばれる1種以上の水不溶性高分子;(d)カルボキシメチルセルロースカルシウム、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロース、架橋カルボキシメチルセルロースナトリウム、結晶セルロース、トウモロコシデンプン、部分アルファー化デンプン、カルボキシメチルスターチナトリウム及び架橋ポリビニルピロリドンからなる群から選ばれる1種以上の崩壊剤;及び(e)滑沢剤の混合物(当該混合物は結合剤、可塑剤、コーティング剤、凝集防止剤、可溶化剤、甘味料、酸味料、矯味剤、pH調整剤、溶解補助剤、着色料及び香料からなる群から選ばれる1種以上の添加物を含有していてもよい)を圧縮成形して得られる口腔内での崩壊時間が60秒以内である口腔内速崩壊性錠;
(19)錠剤100重量部に対し、賦形剤の配合量が30~95重量部、水不溶性高分子の配合量が1~10重量部、崩壊剤の配合量が1~15重量部、滑沢剤の配合量が0.01~3重量部である、前記(18)記載の口腔内速崩壊性錠;
(20)錠剤強度が100~300N/cm2である、前記(19)記載の口腔内速崩壊性錠;
(21)錠剤強度が110~300N/cm2である、前記(19)記載の口腔内速崩壊性錠;
(22)錠剤強度が120~300N/cm2である、前記(19)記載の口腔内速崩壊性錠;
(23)口腔内での崩壊時間が5~45秒である、前記(20)、(21)又は(22)記載の口腔内速崩壊性錠;
(24)口腔内での崩壊時間が5~30秒である、前記(20)、(21)又は(22)記載の口腔内速崩壊性錠;
(25)口腔内での崩壊時間が5~20秒である、前記(20)、(21)又は(22)記載の口腔内速崩壊性錠;
(26)硬度と錠剤重量との比の値が0.2N/mg以上である、前記(20)、(21)又は(22)記載の口腔内速崩壊性錠;
(27)硬度と錠剤重量との比の値が0.3N/mg以上である、前記(20)、(21)又は(22)記載の口腔内速崩壊性錠;
(28)賦形剤がマンニトール、水不溶性高分子がヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート又はカルボキシメチルエチルセルロースである、前記(20)、(21)又は(22)記載の口腔内速崩壊性錠。 The present invention is:
(1) (a) active ingredient; (b) excipient with good wettability in water; (c) water with good moldability and which does not substantially reduce the wettability of the excipient into water. An insoluble polymer; and (d) an intraoral rapidly disintegrating tablet obtained by compression molding a mixture comprising a disintegrant and having an oral disintegration time of 60 seconds or less;
(2) The excipient having good wettability with water is one or more sugar alcohols selected from the group consisting of mannitol, erythritol and xylitol, and the moldability is good and the excipient has good wettability with water. A water-insoluble polymer that does not substantially reduce water is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, ethylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer S, and aminomethacrylate copolymer The intraorally rapidly disintegrating tablet according to (1), which is the above water-insoluble polymer;
(3) 30 to 95 parts by weight of an excipient having good water wettability with respect to 100 parts by weight of the tablet, and substantially good wettability of the excipient with good moldability The intraorally rapidly disintegrating tablet according to the above (1) or (2), wherein the blending amount of the water-insoluble polymer not decreased is 1 to 10 parts by weight, and the blending amount of the disintegrant is 1 to 15 parts by weight;
(4) The intraoral rapidly disintegrating tablet according to (3), wherein the tablet strength is 100 to 300 N / cm 2 ;
(5) The intraoral rapidly disintegrating tablet according to (3), wherein the tablet strength is 110 to 300 N / cm 2 ;
(6) The intraoral rapidly disintegrating tablet according to (3), wherein the tablet strength is 120 to 300 N / cm 2 ;
(7) The intraoral rapidly disintegrating tablet according to (4), (5) or (6), wherein the disintegration time in the oral cavity is 5 to 45 seconds;
(8) The intraoral rapidly disintegrating tablet according to (4), (5) or (6), wherein the disintegration time in the oral cavity is 5 to 30 seconds;
(9) The intraoral rapidly disintegrating tablet according to (4), (5) or (6), wherein the disintegration time in the oral cavity is 5 to 20 seconds;
(10) The intraoral rapidly disintegrating tablet according to (4), (5) or (6), wherein the value of the ratio of hardness to tablet weight is 0.2 N / mg or more;
(11) The rapidly disintegrating tablet in the oral cavity according to the above (4), (5) or (6), wherein the value of the ratio between hardness and tablet weight is 0.3 N / mg or more;
(12) The intraoral rapidly disintegrating tablet according to (4), (5) or (6) above, wherein the active ingredient is nicergoline, imidapril hydrochloride, bisoprolol fumarate, taltileline hydrate, allopurinol or avanafil;
(13) The active ingredient is nicergoline, imidapril hydrochloride, bisoprolol fumarate or taltileline hydrate, and the amount of the active ingredient is 0.1 to 70 parts by weight based on 100 parts by weight of the tablet (11) The intraorally rapidly disintegrating tablets described;
(14) The active ingredient is nicergoline, imidapril hydrochloride, bisoprolol fumarate or taltilelin hydrate, and the amount of the active ingredient is 0.5 to 20 parts by weight based on 100 parts by weight of the tablet (12) The intraorally rapidly disintegrating tablets described;
(15) The active ingredient is nicergoline, imidapril hydrochloride, bisoprolol fumarate or taltileline hydrate, and the amount of the active ingredient is 1 to 15 parts by weight with respect to 100 parts by weight of the tablet. Oral disintegrating tablets;
(16) The active ingredient is nicergoline, imidapril hydrochloride, bisoprolol fumarate or taltilelin hydrate, and the amount of the active ingredient is 1 to 10 parts by weight with respect to 100 parts by weight of the tablet. Oral disintegrating tablets;
(17) The intraoral rapidly disintegrating tablet according to (12), wherein the active ingredient is allopurinol or avanafil, and the amount of the active ingredient is 10 to 50 parts by weight with respect to 100 parts by weight of the tablet;
(18) (a) an active ingredient selected from the group consisting of nicergoline, imidapril hydrochloride, bisoprolol fumarate, tartyreline hydrate, allopurinol and avanafil; (b) one or more selected from the group consisting of mannitol, erythritol and xylitol Excipient; (c) one or more water-insolubles selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, ethylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer S and aminomethacrylate copolymer Polymer: (d) carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, carboxymethylcellulose, crosslinked carboxymethyl One or more disintegrants selected from the group consisting of sodium roulose, crystalline cellulose, corn starch, partially pregelatinized starch, sodium carboxymethyl starch and crosslinked polyvinylpyrrolidone; and (e) a mixture of lubricants (the mixture is a binder) Contains one or more additives selected from the group consisting of a plasticizer, a coating agent, an anti-aggregation agent, a solubilizer, a sweetener, a sour agent, a corrigent, a pH adjuster, a solubilizer, a colorant, and a fragrance. Orally disintegrating time obtained by compression molding the oral disintegration tablet within 60 seconds;
(19) 30 to 95 parts by weight of excipient, 1 to 10 parts by weight of water-insoluble polymer, 1 to 15 parts by weight of disintegrant, The intraorally rapidly disintegrating tablet according to (18), wherein the amount of the blending agent is 0.01 to 3 parts by weight;
(20) The intraoral rapidly disintegrating tablet according to (19), wherein the tablet strength is 100 to 300 N / cm 2 ;
(21) The intraorally rapidly disintegrating tablet according to (19), wherein the tablet strength is 110 to 300 N / cm 2 ;
(22) The intraoral rapidly disintegrating tablet according to (19), wherein the tablet strength is 120 to 300 N / cm 2 ;
(23) The intraoral rapidly disintegrating tablet according to (20), (21) or (22), wherein the disintegration time in the oral cavity is 5 to 45 seconds;
(24) The intraoral rapidly disintegrating tablet according to (20), (21) or (22), wherein the disintegration time in the oral cavity is 5 to 30 seconds;
(25) The intraoral rapidly disintegrating tablet according to (20), (21) or (22), wherein the disintegration time in the oral cavity is 5 to 20 seconds;
(26) The intraorally rapidly disintegrating tablet according to (20), (21) or (22), wherein the value of the ratio of hardness to tablet weight is 0.2 N / mg or more;
(27) The intraoral rapidly disintegrating tablet according to (20), (21) or (22), wherein the value of the ratio of hardness to tablet weight is 0.3 N / mg or more;
(28) The intraoral rapid disintegration according to (20), (21) or (22) above, wherein the excipient is mannitol and the water-insoluble polymer is hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate or carboxymethylethylcellulose. Sex tablets.
(30)活性成分がニセルゴリン、塩酸イミダプリル、フマル酸ビソプロロール、タルチレリン水和物、アロプリノール又はアバナフィルであり、水への濡れ性が良好な賦形剤がマンニトール、エリスリトール又はキシリトールであり、成形性が良好で前記賦形剤の水への濡れ性を実質的に低下させない水不溶性高分子がヒドロキシプロピルメチルセルロースアセテートサクシネート、エチルセルロース、ヒドロキシプロピルメチルセルロースフタレート、カルボキシメチルエチルセルロース、メタクリル酸コポリマーL、メタクリル酸コポリマーS及びアミノメタクリレートコポリマーからなる群から選ばれる1種以上の水不溶性高分子であり、崩壊剤がカルボキシメチルセルロースカルシウム、カルボキシメチルセルロース、架橋カルボキシメチルセルロースナトリウム、カルボキシメチルスターチナトリウム又は架橋ポリビニルピロリドンである、前記(29)記載の製造方法;
(31)口腔内速崩壊性錠の錠剤強度が100~300N/cm2である、前記(30)記載の製造方法;及び
(32)直径5~10mm、重量100~300mgの錠剤であって、硬度が15N~90Nである前記(1)又は(18)記載の口腔内速崩壊性錠
に関する。 (29) i) (a) active ingredient; (b) excipient with good wettability in water; (c) good moldability and substantially reduced wettability of the excipient in water A water-insoluble polymer which is not allowed to be used; and (d) a mixture of disintegrants (the mixture is a lubricant, a binder, a plasticizer, a coating agent, an anti-aggregation agent, a solubilizer, a sweetener, an acidulant, a corrigent, pH adjustment) Preparing one or more additives selected from the group consisting of agents, solubilizers, colorants and fragrances), and then ii) compression-molding the mixture obtained in i) above. A process for producing a rapidly disintegrating tablet in the oral cavity, wherein the disintegration time in the oral cavity is within 60 seconds;
(30) The active ingredient is nicergoline, imidapril hydrochloride, bisoprolol fumarate, taltyreline hydrate, allopurinol or avanafil, and the excipient with good wettability to water is mannitol, erythritol or xylitol, and the moldability is good And the water-insoluble polymer that does not substantially reduce the wettability of the excipient in water is hydroxypropylmethylcellulose acetate succinate, ethylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer S and One or more water-insoluble polymers selected from the group consisting of amino methacrylate copolymers, and the disintegrant is carboxymethylcellulose calcium, carboxymethylcellulose, crosslinked carbo Shi cellulose sodium, carboxymethyl starch sodium or crosslinked polyvinylpyrrolidone, the (29) The process according;
(31) The production method according to the above (30), wherein the tablet strength of the orally rapidly disintegrating tablet is 100 to 300 N / cm 2 ; and (32) a tablet having a diameter of 5 to 10 mm and a weight of 100 to 300 mg, The invention relates to the intraorally rapidly disintegrating tablet according to the above (1) or (18), which has a hardness of 15 N to 90 N.
A)活性成分(a)と水への濡れ性が良好な賦形剤(b)との混合物に、成形性が良好で前記賦形剤の水への濡れ性を実質的に低下させない水不溶性高分子(c)の溶液(例えば、エタノール/水溶液等)又は水分散液を添加しつつ造粒し、造粒物を乾燥後、得られた顆粒と崩壊剤、並びに要すればその他所望の添加物(滑沢剤、甘味料、有機酸の如き酸味料等)とを混合し、当該混合物を圧縮成形するか、或いは
B)成形性が良好で且つ水への濡れ性が良好な賦形剤(b)に、成形性が良好で前記賦形剤の水への濡れ性を実質的に低下させない水不溶性高分子(c)の溶液(例えば、エタノール/水溶液等)又は水分散液を添加しつつ造粒し、造粒物を乾燥後、得られた顆粒と活性成分(a)、崩壊剤、並びに要すればその他所望の添加物(滑沢剤、甘味料、有機酸の如き酸味料等)とを混合し、当該混合物を圧縮成形することにより製することができる。尚、上記製造方法において、活性成分又はその他の添加物は、必要に応じ、エチルセルロースの如きフィルム形成性ポリマー等でコーティングされていてもよい。 About the manufacturing method of the intraoral quick disintegrating tablet of this invention, it will be as follows if one of the aspects is demonstrated more concretely. That is, the intraoral rapidly disintegrating tablet of the present invention is, for example,
A) Water-insoluble in a mixture of the active ingredient (a) and an excipient (b) having good wettability to water, which has good moldability and does not substantially reduce the wettability of the excipient to water. Granulate while adding polymer (c) solution (for example, ethanol / water solution) or aqueous dispersion, and after drying the granulated product, the resulting granule and disintegrant, and other desired additions as required Or a mixture of a product (a lubricant, a sweetener, a sour agent such as an organic acid, etc.) and compression-molding the mixture, or B) an excipient having good moldability and good wettability to water In (b), a solution of a water-insoluble polymer (c) that has good moldability and does not substantially reduce the wettability of the excipient to water (for example, an ethanol / water solution) or an aqueous dispersion is added. After granulating and drying the granulated product, the resulting granules, the active ingredient (a), a disintegrant, and other desired additives as required (Lubricants, sweeteners, acidulants such as organic acids, etc.) can be mixed, and the mixture can be compression-molded. In the above production method, the active ingredient or other additives may be coated with a film-forming polymer such as ethyl cellulose, if necessary.
賦形剤97重量部(又は90重量部)と水不溶性高分子(ヒドロキシプロピルメチルセルロースアセテートサクシネート、HPMC-AS、グレード;HF)3重量部(又は10重量部)の混合物300mgをコンパクションアナライザー(菊水製作所製、平面杵:直径10mm)を用いて、打錠圧1000kg/杵で圧縮成形することにより、錠剤を得た。各錠剤の水への濡れ性(濡れ時間)及び硬度を、それぞれ下記の評価方法に従って測定し、当該測定結果(下記表1)をもとに、賦形剤を次の2つのグループに分類した。
グループA: 錠剤の濡れ時間が300秒以内、かつ錠剤硬度が賦形剤単独の3倍以上である、水不溶性高分子含有時の水への濡れ性及び成形性が良好な賦形剤。
グループB: 錠剤の濡れ時間が300秒以上、又は錠剤硬度が賦形剤単独の3倍以下である、水不溶性高分子含有時の水への濡れ性又は成形性が不良な賦形剤。
評価方法:
a)錠剤の水への濡れ性(濡れ時間)
錠剤の水への濡れ性(濡れ時間)は、公知の方法〔Chem.Pharm.Bull.44(1),2121-2127(1996)〕に準じて、以下のように測定した。即ち、秤量皿に精製水6mLを入れ、その中にティシュ・ペーパー(205mm×120mm、キムワイプS-200、日本製紙クレシア製)を4つ折りにして敷き、これを完全に濡らした後、この上に錠剤1錠を静置し、錠剤全体が湿潤するまでに要した時間(濡れ時間)を測定した。 Experimental example 1
300 mg of a mixture of 97 parts by weight (or 90 parts by weight) of excipient and 3 parts by weight (or 10 parts by weight) of a water-insoluble polymer (hydroxypropylmethylcellulose acetate succinate, HPMC-AS, grade; HF) is applied to a compaction analyzer (Kikusui). Tablets were obtained by compression molding with a tableting pressure of 1000 kg / 杵 using a flat plate made by Seisakusho (diameter: 10 mm in diameter). Water wettability (wetting time) and hardness of each tablet were measured according to the following evaluation methods, respectively, and the excipients were classified into the following two groups based on the measurement results (Table 1 below). .
Group A: An excipient having good wettability to water and moldability when containing a water-insoluble polymer, wherein the tablet wetting time is within 300 seconds and the tablet hardness is 3 times or more of the excipient alone.
Group B: An excipient having poor wettability to water or moldability when containing a water-insoluble polymer, wherein the tablet wetting time is 300 seconds or more, or the tablet hardness is 3 times or less of the excipient alone.
Evaluation methods:
a) Water wettability of tablets (wetting time)
The wettability (wetting time) of the tablet with water is determined by a known method [Chem. Pharm. Bull. 44 (1), 2121-2127 (1996)], the measurement was performed as follows. That is, 6 mL of purified water is put in a weighing dish, and tissue paper (205 mm × 120 mm, Kimwipe S-200, manufactured by Nippon Paper Crecia) is folded in four and spread on it. One tablet was allowed to stand, and the time (wetting time) required until the entire tablet was wet was measured.
錠剤の硬度は、錠剤硬度計(Schleuniger社製、型式:6D)を用いて測定した。測定は3回行い、その平均値をもってその錠剤の硬度とした。 b) Tablet hardness The tablet hardness was measured using a tablet hardness tester (manufactured by Schleuniger, model: 6D). The measurement was performed three times, and the average value was taken as the hardness of the tablet.
D-マンニトール97重量部と各種水不溶性高分子3重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加してステンレス容器中で練合した後、日本薬局方22号篩で整粒し、得られた造粒物を通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。この造粒顆粒300mgをコンパクションアナライザー(菊水製作所製)で圧縮成形(平面杵:直径10mm、打錠圧:1000kg/杵)することにより、錠剤を得た。各錠剤の水への濡れ性(濡れ時間)及び硬度を実験例1に記載の評価方法に従って測定した。また当該測定結果(下記表2)に基づき、水不溶性高分子を以下の3つのグループに分類した。
グループ1:
錠剤の濡れ時間が300秒以内、錠剤硬度がマンニトール単独の3倍以上である、糖アルコールの水への濡れ性を低下させず、かつ成形性が良好な水不溶性高分子。
グループ2:
水不溶性高分子を含有する錠剤の濡れ時間が300秒以内、錠剤硬度がマンニトール単独の3倍以下である、糖アルコールの水への濡れ性を低下させないが、成形性が不良である水不溶性高分子。
グループ3:
水不溶性高分子を含有する錠剤の濡れ時間が300秒以上、錠剤硬度がマンニトール単独の3倍以上である、糖アルコールの水への濡れ性を低下させるが、成形性が良好である水不溶性高分子。 Experimental example 2
To a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of various water-insoluble polymers, 5 parts by weight of 80% (W / W) aqueous ethanol solution was added and kneaded in a stainless steel container. The granulated product obtained was granulated by drying in a ventilated box dryer at 50 ° C. for 2 hours. 300 mg of this granulated granule was compression-molded with a compaction analyzer (manufactured by Kikusui Seisakusho) (plane wrinkle: diameter 10 mm, tableting pressure: 1000 kg / mm) to obtain tablets. The wettability (wetting time) and hardness of each tablet in water were measured according to the evaluation method described in Experimental Example 1. Based on the measurement results (Table 2 below), the water-insoluble polymers were classified into the following three groups.
Group 1:
A water-insoluble polymer having a tablet wetting time of 300 seconds or less, a tablet hardness of 3 times or more that of mannitol alone, and having good moldability without reducing the wettability of sugar alcohol with water.
Group 2:
Tablets containing water-insoluble polymers have a wetting time of less than 300 seconds, and tablet hardness is 3 times or less that of mannitol alone, but do not reduce the wettability of sugar alcohol to water, but have poor moldability. molecule.
Group 3:
A tablet containing a water-insoluble polymer has a wetting time of 300 seconds or more and a tablet hardness of 3 times or more that of mannitol alone. molecule.
実験例1に記載の各種賦形剤と水不溶性高分子(HPMC-AS/HF)を用い、実施例1~3及び比較例1~2に記載した方法で錠剤を得た。当該錠剤の硬度を実験例1に記載の評価方法と同様にして測定した。また、当該錠剤の口腔内での崩壊時間を以下のようにして測定した。
口腔内での崩壊時間:
健康な成人男子(3人)がそれぞれ錠剤1錠を口に含み、口中に静置させた状態(噛む、舌を激しく動かす等の行為をしない)で、唾液により、錠剤が完全に崩壊するまでの時間を測定し、その平均値を算出した。 Experimental example 3
Using various excipients described in Experimental Example 1 and a water-insoluble polymer (HPMC-AS / HF), tablets were obtained by the methods described in Examples 1-3 and Comparative Examples 1-2. The hardness of the tablet was measured in the same manner as the evaluation method described in Experimental Example 1. Moreover, the disintegration time in the oral cavity of the tablet was measured as follows.
Disintegration time in the oral cavity:
Healthy adult males (3 persons) each containing one tablet in their mouth and left in the mouth (does not chew, move the tongue violently, etc.) until the tablet is completely disintegrated by saliva Was measured and the average value was calculated.
各錠剤の硬度及び口腔内での崩壊時間は下記表3の通りである。表3から明らかな通り、グループAの賦形剤を用いて得られた錠剤(実施例1~3の錠剤)の場合、いずれも硬度が40N以上で、かつ口腔内での崩壊時間は15~42秒であり、口腔内崩壊性製剤として良好な特性を示した。一方、グループBに分類される賦形剤を用いた錠剤(比較例1~2の錠剤)の場合、硬度は50N以上であったが、口腔内での崩壊時間は60秒を超えるものとなり、口腔内崩壊性製剤として実用上十分な特性を有していなかった。これらの試験結果より、本発明による口腔内崩壊性製剤に適用する賦形剤としては、グループAに分類される賦形剤が好ましいことが分かった。 result)
The hardness of each tablet and the disintegration time in the oral cavity are as shown in Table 3 below. As is apparent from Table 3, in the case of tablets obtained using Group A excipients (tablets of Examples 1 to 3), the hardness was 40 N or more and the disintegration time in the oral cavity was 15 to It was 42 seconds and showed good characteristics as an orally disintegrating preparation. On the other hand, in the case of tablets using the excipients classified in Group B (tablets of Comparative Examples 1 and 2), the hardness was 50 N or more, but the disintegration time in the oral cavity exceeded 60 seconds, It did not have practically sufficient characteristics as an orally disintegrating preparation. From these test results, it was found that excipients classified into Group A are preferable as excipients applied to the orally disintegrating preparation according to the present invention.
実験例2に記載の各種水不溶性高分子と賦形剤(D-マンニトール)を用い、実施例1、4~12及び比較例3~6に記載した方法で錠剤を得た。当該錠剤の硬度及び口腔内での崩壊時間に関する比較試験結果を下記表4に示した。 Experimental Example 4
Using various water-insoluble polymers described in Experimental Example 2 and an excipient (D-mannitol), tablets were obtained by the methods described in Examples 1, 4 to 12 and Comparative Examples 3 to 6. The comparative test results regarding the hardness of the tablets and the disintegration time in the oral cavity are shown in Table 4 below.
下記表5~7記載の成分を用いて、後記実施例13~27に記載の各方法で口腔内速崩壊性錠を得た。 Experimental Example 5
Using the ingredients shown in Tables 5 to 7 below, oral disintegrating tablets were obtained by the methods described in Examples 13 to 27 below.
アバナフィル(活性成分、化学名:(S)-2-[2-ヒドロキシメチル-1-ピロリジニル-4-(3-クロロ-4-メトキシベンジルアミノ)-5-[N-(2-ピリミジニルメチル)カルバモイル]ピリミジン)、D-マンニトール(賦形剤)及びHPMCAS/HF(水不溶性高分子)を含有する口腔内速崩壊性錠を、後記実施例28~30に記載した方法で得た。当該口腔内速崩壊性錠の処方成分と配合量、並びに各錠剤の特性は、それぞれ下記表11及び表12に示した通りである。 Experimental Example 6
Avanafil (active ingredient, chemical name: (S) -2- [2-hydroxymethyl-1-pyrrolidinyl-4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] ] Orally rapidly disintegrating tablets containing pyrimidine), D-mannitol (excipient) and HPMCAS / HF (water-insoluble polymer) were obtained by the method described in Examples 28 to 30 below. The prescription components and blending amount of the intraoral rapidly disintegrating tablet and the characteristics of each tablet are as shown in Table 11 and Table 12, respectively.
塩酸イミダプリル、D-マンニトール(賦形剤)、HPMCAS/HF又はEC#10(水不溶性高分子)を含有する口腔内速崩壊性錠を、後記実施例31~34に記載した方法で得た。当該口腔内速崩壊性錠の処方成分と配合量、並びに各錠剤の特性は、それぞれ下記表13及び表14に示した通りである。 Experimental Example 7
Orally rapidly disintegrating tablets containing imidapril hydrochloride, D-mannitol (excipient), HPMCAS / HF or EC # 10 (water-insoluble polymer) were obtained by the methods described in Examples 31 to 34 below. The prescription components and blending amounts of the intraoral rapidly disintegrating tablet and the characteristics of each tablet are as shown in Table 13 and Table 14 below, respectively.
実施例28~34で得られた各錠剤を25℃/75%RHの条件下で1ヶ月間保存した後、硬度及び口腔内での崩壊時間を測定した(表12及び表14参照)。その結果、これらの錠剤に関して、口腔内での崩壊時間の遅延は観察されず、また硬度の低下も僅かであった。これらの結果から、本発明の口腔内速崩壊性錠は、PTP包装から錠剤を取出してから自動錠剤分包機中の大気雰囲気に曝される期間、並びに分包後服用されるまでの期間を通じて、口腔内速崩壊性錠として好適な崩壊性が維持され、かつ取り扱い上十分な硬度が維持され得るものであることが確認された。 Experimental Example 8
Each tablet obtained in Examples 28 to 34 was stored for 1 month at 25 ° C./75% RH, and then the hardness and disintegration time in the oral cavity were measured (see Tables 12 and 14). As a result, regarding these tablets, no delay in the disintegration time in the oral cavity was observed, and the decrease in hardness was slight. From these results, the intraoral rapidly disintegrating tablet of the present invention is exposed to the atmospheric atmosphere in the automatic tablet packaging machine after taking out the tablet from the PTP packaging, and through the period until it is taken after packaging. It was confirmed that the disintegrability suitable as an intraoral quick disintegrating tablet was maintained and the hardness sufficient for handling could be maintained.
(1)日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール97重量部及びヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;HF)3重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加しつつ造粒後、通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。 Example 1
(1) 80% of 5 parts by weight in a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of hydroxypropylmethylcellulose acetate succinate (grade: HF) sieved with a 22-mesh screen of Japanese Pharmacopoeia (opening: 710 μm) ( W / W) After granulation while adding an aqueous ethanol solution, the granulated granule was obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
(1)日本薬局方60メッシュ篩(目開き:250μm)で篩過したエリスリトール90重量部及びヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;HF)10重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加しつつ造粒後、通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。
(2)上記(1)の造粒顆粒283.5重量部、クロスポビドン15重量部及びステアリン酸マグネシウム1.5重量部を混合し、打錠用顆粒を得た。該打錠用顆粒を用い、1錠当たり300mgとなるよう、コンパクションアナライザー(菊水製作所製、杵:直径10mm、打錠圧:1000kg/杵)で圧縮成形することにより、口腔内速崩壊性錠を得た(硬度:51N、口腔内での崩壊時間:15秒)。 Example 2
(1) 5 parts by weight of 80% (W / W) in a mixture of 90 parts by weight of erythritol and 10 parts by weight of hydroxypropyl methylcellulose acetate succinate (grade; HF) sieved with a 60-mesh screen of Japanese Pharmacopoeia (opening: 250 μm) W) After granulation while adding an aqueous ethanol solution, granulation granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
(2) 283.5 parts by weight of the granulated granules (1), 15 parts by weight of crospovidone and 1.5 parts by weight of magnesium stearate were mixed to obtain granules for tableting. By using the granules for tableting and compression-molding with a compaction analyzer (manufactured by Kikusui Seisakusho, 杵: diameter 10 mm, tableting pressure: 1000 kg / 杵) to give 300 mg per tablet, Obtained (hardness: 51 N, disintegration time in the oral cavity: 15 seconds).
(1)顆粒の調製
メノウ乳鉢を用いて粉砕後に日本薬局方60メッシュ篩(目開き:250μm)で篩過したキシリトール90重量部、並びにヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;HF)10重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加しつつ造粒後、通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。
(2)口腔内速崩壊性錠の調製
上記(1)の造粒顆粒283.5重量部、クロスポビドン15重量部及びステアリン酸マグネシウム1.5重量部を混合し、打錠用顆粒を得た。該打錠用顆粒を用い、1錠当たり300mgとなるよう、コンパクションアナライザー(菊水製作所製、杵:直径10mm、打錠圧:2000kg/杵)で圧縮成形することにより、口腔内速崩壊性錠を得た(硬度:44N、口腔内での崩壊時間:42秒)。 Example 3
(1) Preparation of granules 90 parts by weight of xylitol, which was pulverized using an agate mortar and then sieved with a Japanese pharmacopoeia 60 mesh sieve (opening: 250 μm), and 10 parts by weight of hydroxypropylmethylcellulose acetate succinate (grade; HF) After granulation while adding 5 parts by weight of 80% (W / W) aqueous ethanol solution to the mixture, granulation granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
(2) Preparation of intraorally rapidly disintegrating tablets 283.5 parts by weight of the granulated granules of (1) above, 15 parts by weight of crospovidone and 1.5 parts by weight of magnesium stearate were mixed to obtain granules for tableting. . By using the granules for tableting and compression molding with a compaction analyzer (manufactured by Kikusui Seisakusho, 杵: diameter 10 mm, tableting pressure: 2000 kg / 杵) to give 300 mg per tablet, Obtained (hardness: 44 N, disintegration time in the oral cavity: 42 seconds).
(1)日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール97重量部及びヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;MF)3重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加しつつ造粒後、通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。 Example 4
(1) 80% of 5 parts by weight in a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of hydroxypropylmethylcellulose acetate succinate (grade; MF) sieved with a Japanese pharmacopoeia 22 mesh sieve (aperture: 710 μm) W / W) After granulation while adding an aqueous ethanol solution, the granulated granule was obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
(1)日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール97重量部及びヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;LF)3重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加しつつ造粒後、通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。 Example 5
(1) 80% of 5 parts by weight in a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of hydroxypropylmethylcellulose acetate succinate (grade; LF) sieved with a Japanese pharmacopoeia 22 mesh sieve (aperture: 710 μm) W / W) After granulation while adding an aqueous ethanol solution, the granulated granule was obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
(1)日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール97重量部及びエチルセルロース3重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加しつつ造粒後、通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。 Example 6
(1) While adding 5 parts by weight of 80% (W / W) ethanol aqueous solution to a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of ethylcellulose sieved with a 22-mesh sieve (mesh size: 710 μm) After granulation, the granulated granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
(1)日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール97重量部及びメノウ乳鉢で粉砕したヒドロキシプロピルメチルセルロースフタレート(グレード;HP-50)3重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加しつつ造粒後、通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。 Example 7
(1) 5 parts by weight in a mixture of 97 parts by weight of D-mannitol sieved with a Japanese pharmacopoeia 22 mesh sieve (aperture: 710 μm) and 3 parts by weight of hydroxypropyl methylcellulose phthalate (grade; HP-50) ground with an agate mortar After granulating while adding 80% (W / W) aqueous ethanol solution, granulated granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
(1)日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール97重量部及びアミノメタクリレートコポリマー(オイドラギットRSPO)3重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加しつつ造粒後、通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。 Example 8
(1) 80% (W / W) of 5 parts by weight in a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of aminomethacrylate copolymer (Eudragit RSPO) sieved with a 22-mesh pharmacopoeia (mesh size: 710 μm) After granulation while adding an aqueous ethanol solution, the granulated granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
(1)日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール97重量部及びアミノメタクリレートコポリマー(オイドラギットRLPO)3重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加しつつ造粒後、通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。 Example 9
(1) 80% (W / W) of 5 parts by weight in a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of aminomethacrylate copolymer (Eudragit RLPO) sieved with a 22-mesh screen of Japanese Pharmacopoeia (aperture: 710 μm) After granulation while adding an aqueous ethanol solution, the granulated granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
(1)日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール97重量部及びメタクリル酸コポリマー(オイドラギットL100)3重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加しつつ造粒後、通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。 Example 10
(1) 5% by weight of 80% (W / W) in a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of methacrylic acid copolymer (Eudragit L100) sieved with a 22-mesh sieve of Japanese Pharmacopoeia (opening: 710 μm) After granulation while adding an aqueous ethanol solution, the granulated granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
(1)日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール97重量部及びメタクリル酸コポリマー(オイドラギットS100)3重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加しつつ造粒後、通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。 Example 11
(1) 5 parts by weight of 80% (W / W) in a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of methacrylic acid copolymer (Eudragit S100) sieved with a Japanese pharmacopoeia 22 mesh sieve (aperture: 710 μm) After granulation while adding an aqueous ethanol solution, the granulated granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
(1)日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール97重量部及びカルボキシメチルエチルセルロース3重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加しつつ造粒後、通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。 Example 12
(1) 5 parts by weight of 80% (W / W) ethanol aqueous solution was added to a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of carboxymethyl ethyl cellulose sieved with a 22-mesh sieve (mesh size: 710 μm). Then, after granulation, granulated granules were obtained by drying at 50 ° C. for 2 hours in a ventilated box dryer.
(1)塩酸イミダプリル1.8重量部及び日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール95重量部を流動層造粒機(パウレック製、MP-01/03)に仕込み、給気温度60℃で、8%ヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;HF)の80%(W/W)エタノール水溶液39.7重量部を約30分間かけて噴霧しながら造粒した。造粒物の温度が40℃以上になるまで乾燥することにより、造粒顆粒を得た。 Example 13
(1) 1.8 parts by weight of imidapril hydrochloride and 95 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (aperture: 710 μm) were placed in a fluidized bed granulator (manufactured by Paulec, MP-01 / 03). The mixture was granulated while spraying 39.7 parts by weight of an aqueous solution of 80% (W / W) ethanol of 8% hydroxypropylmethylcellulose acetate succinate (grade; HF) at an air supply temperature of 60 ° C. over about 30 minutes. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
(1)塩酸イミダプリル1.8重量部及び日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール95重量部を流動層造粒機(パウレック製、MP-01/03)に仕込み、給気温度60℃で、8%ヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;MF)の80%(W/W)エタノール水溶液39.7重量部を約30分間かけて噴霧しながら造粒した。造粒物の温度が40℃以上になるまで乾燥することにより、造粒顆粒を得た。 Example 14
(1) 1.8 parts by weight of imidapril hydrochloride and 95 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (aperture: 710 μm) were placed in a fluidized bed granulator (manufactured by Paulec, MP-01 / 03). The mixture was granulated while spraying 39.7 parts by weight of an 80% (W / W) ethanol aqueous solution of 8% hydroxypropylmethylcellulose acetate succinate (grade; MF) at a supply air temperature of 60 ° C. over about 30 minutes. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
(1)塩酸イミダプリル1.8重量部及び日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール95重量部を流動層造粒機(パウレック製、MP-01/03)に仕込み、給気温度60℃で、8%ヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;LF)の80%(W/W)エタノール水溶液39.7重量部を約30分間かけて噴霧しながら造粒した。造粒物の温度が40℃以上になるまで乾燥することにより、造粒顆粒を得た。 Example 15
(1) 1.8 parts by weight of imidapril hydrochloride and 95 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (aperture: 710 μm) were placed in a fluidized bed granulator (manufactured by Paulec, MP-01 / 03). The mixture was granulated while spraying 39.7 parts by weight of an 80% (W / W) ethanol aqueous solution of 8% hydroxypropylmethylcellulose acetate succinate (grade; LF) at an air supply temperature of 60 ° C. over about 30 minutes. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
(1)塩酸イミダプリル1.8重量部及び日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール95重量部を流動層造粒機(パウレック製、MP-01/03)に仕込み、給気温度60℃で、8%ヒドロキシプロピルメチルセルロースフタレート(グレード;HP-50)の80%(W/W)エタノール水溶液39.7重量部を約30分間かけて噴霧しながら造粒した。造粒物の温度が40℃以上になるまで乾燥することにより、造粒顆粒を得た。 Example 16
(1) 1.8 parts by weight of imidapril hydrochloride and 95 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (aperture: 710 μm) were placed in a fluidized bed granulator (manufactured by Paulec, MP-01 / 03). The mixture was charged and granulated while spraying 39.7 parts by weight of an 80% (W / W) ethanol aqueous solution of 8% hydroxypropylmethylcellulose phthalate (grade: HP-50) at an air supply temperature of 60 ° C. over about 30 minutes. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
(1)塩酸イミダプリル1.8重量部及び日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール95重量部を流動層造粒機(パウレック製、MP-01/03)に仕込み、給気温度60℃で、8%アミノメタクリレートコポリマー(オイドラギットRSPO)の80%(W/W)エタノール水溶液39.7重量部を約30分間かけて噴霧しながら造粒した。造粒物の温度が40℃以上になるまで乾燥することにより、造粒顆粒を得た。 Example 17
(1) 1.8 parts by weight of imidapril hydrochloride and 95 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (aperture: 710 μm) were placed in a fluidized bed granulator (manufactured by Paulec, MP-01 / 03). The mixture was granulated while spraying 39.7 parts by weight of an 80% (W / W) ethanol aqueous solution of 8% amino methacrylate copolymer (Eudragit RSPO) at an air supply temperature of 60 ° C. over about 30 minutes. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
(1)塩酸イミダプリル1.8重量部及び日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール95重量部を流動層造粒機(パウレック製、MP-01/03)に仕込み、給気温度60℃で、8%カルボキシメチルエチルセルロースの80%(W/W)エタノール水溶液39.7重量部を約30分間かけて噴霧しながら造粒した。造粒物の温度が40℃以上になるまで乾燥することにより、造粒顆粒を得た。 Example 18
(1) 1.8 parts by weight of imidapril hydrochloride and 95 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (aperture: 710 μm) were placed in a fluidized bed granulator (manufactured by Paulec, MP-01 / 03). The mixture was granulated while spraying 39.7 parts by weight of an 80% (W / W) ethanol solution of 8% carboxymethylethylcellulose at an air supply temperature of 60 ° C. over about 30 minutes. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
(1)実施例14(1)の造粒顆粒283.5重量部、カルボキシメチルセルロース15重量部及びステアリン酸マグネシウム1.5重量部を混合し、打錠用顆粒を得た。当該打錠用顆粒を用い、1錠当たり300mgとなるよう、コンパクションアナライザー(菊水製作所製、杵:直径10mm、打錠圧:800kg/杵)で圧縮成形することにより、口腔内速崩壊性錠を得た(硬度:50N、口腔内での崩壊時間:23秒)。 Example 19
(1) 283.5 parts by weight of the granulated granules of Example 14 (1), 15 parts by weight of carboxymethyl cellulose and 1.5 parts by weight of magnesium stearate were mixed to obtain granules for tableting. By using the granules for tableting and compression molding with a compaction analyzer (manufactured by Kikusui Seisakusho, 杵: diameter 10 mm, tableting pressure: 800 kg / 杵) to give 300 mg per tablet, Obtained (hardness: 50 N, disintegration time in the oral cavity: 23 seconds).
(1)実施例14(1)の造粒顆粒283.5重量部、クロスカルメロースナトリウム6重量部及びステアリン酸マグネシウム1.5重量部を混合し、打錠用顆粒を得た。当該打錠用顆粒を用い、1錠当たり291mgとなるよう、コンパクションアナライザー(菊水製作所製、杵:直径10mm、打錠圧:800kg/杵)で圧縮成形することにより、口腔内速崩壊性錠を得た(硬度:52N、口腔内での崩壊時間:20秒)。 Example 20
(1) 283.5 parts by weight of granulated granules of Example 14 (1), 6 parts by weight of croscarmellose sodium and 1.5 parts by weight of magnesium stearate were mixed to obtain granules for tableting. By using the granules for tableting and compression molding with a compaction analyzer (manufactured by Kikusui Seisakusho, 杵: diameter 10 mm, tableting pressure: 800 kg / 杵) to give 291 mg per tablet, Obtained (hardness: 52 N, disintegration time in the oral cavity: 20 seconds).
(1)実施例14(1)の造粒顆粒283.5重量部、カルメロースカルシウム15重量部及びステアリン酸マグネシウム1.5重量部を混合し、打錠用顆粒を得た。当該打錠用顆粒を用い、1錠当たり300mgとなるよう、コンパクションアナライザー(菊水製作所製、杵:直径10mm、打錠圧:800kg/杵)で圧縮成形することにより、口腔内速崩壊性錠を得た(重量:300mg、硬度:50N、口腔内での崩壊時間:28秒)。 Example 21
(1) 283.5 parts by weight of granulated granules of Example 14 (1), 15 parts by weight of carmellose calcium and 1.5 parts by weight of magnesium stearate were mixed to obtain granules for tableting. By using the granules for tableting and compression molding with a compaction analyzer (manufactured by Kikusui Seisakusho, 杵: diameter 10 mm, tableting pressure: 800 kg / 杵) to give 300 mg per tablet, Obtained (weight: 300 mg, hardness: 50 N, disintegration time in the oral cavity: 28 seconds).
(1)実施例14(1)の造粒顆粒283.5重量部、カルボキシメチルスターチナトリウム9重量部及びステアリン酸マグネシウム1.5重量部を混合し、打錠用顆粒を得た。当該打錠用顆粒を用い、1錠当たり294mgとなるよう、コンパクションアナライザー(菊水製作所製、杵:直径10mm、打錠圧:850kg/杵)で圧縮成形することにより、口腔内速崩壊性錠を得た(硬度:53N、口腔内での崩壊時間:29秒)。 Example 22
(1) 283.5 parts by weight of granulated granules of Example 14 (1), 9 parts by weight of sodium carboxymethyl starch and 1.5 parts by weight of magnesium stearate were mixed to obtain granules for tableting. By using the granules for tableting and compression-molding with a compaction analyzer (Kikusui Seisakusho, 杵: diameter 10 mm, tableting pressure: 850 kg / よ う) to give 294 mg per tablet, Obtained (hardness: 53 N, disintegration time in the oral cavity: 29 seconds).
(1)フマル酸ビソプロロール1.8重量部及び日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール95重量部を流動層造粒機(パウレック製、MP-01/03)に仕込み、給気温度60℃で、8%ヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;HF)80%(W/W)エタノール水溶液39.7重量部を約30分間かけて噴霧し、造粒した。造粒物の温度が40℃以上になるまで乾燥することにより、造粒顆粒を得た。 Example 23
(1) Fluidized bed granulator (manufactured by Paulek, MP-01 / 03) was added 1.8 parts by weight of bisoprolol fumarate and 95 parts by weight of D-mannitol sieved with Japanese Pharmacopoeia 22 mesh sieve (mesh size: 710 μm). Then, 39.7 parts by weight of an 8% hydroxypropylmethylcellulose acetate succinate (grade; HF) 80% (W / W) ethanol aqueous solution was sprayed over about 30 minutes at an air supply temperature of 60 ° C. and granulated. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
(1)フマル酸ビソプロロール2重量部、日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール88重量部及びメタクリル酸コポリマーL(オイドラギット L)10重量部を流動層造粒機(パウレック製、MP-01/03)に仕込み、給気温度60℃で、精製水54.1重量部を約25分間かけて噴霧しながら造粒後、造粒物の温度が40℃以上になるまで乾燥することにより、造粒顆粒を得た。 Example 24
(1) Fluidized bed granulator comprising 2 parts by weight of bisoprolol fumarate, 88 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (mesh opening: 710 μm) and 10 parts by weight of methacrylic acid copolymer L (Eudragit L) (Powrec, MP-01 / 03), granulated while spraying 54.1 parts by weight of purified water over a period of about 25 minutes at an air supply temperature of 60 ° C, and then the temperature of the granulated product is 40 ° C or higher By drying to the end, granulated granules were obtained.
(1)日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール97重量部を流動層造粒機(パウレック製,MP-01/03)に仕込み、給気温度60℃で、8%ヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;HF)の80%(W/W)エタノール水溶液37.5重量部を約30分間かけて噴霧しつつ造粒後、造粒物の温度が40℃以上になるまで乾燥することにより、造粒顆粒を得た。 Example 25
(1) 97 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (aperture: 710 μm) was charged into a fluidized bed granulator (manufactured by Pauleck, MP-01 / 03) at an air supply temperature of 60 ° C. After granulation while spraying 37.5 parts by weight of 8% hydroxypropylmethylcellulose acetate succinate (grade; HF) 80% (W / W) ethanol aqueous solution over about 30 minutes, the temperature of the granulated product is 40 ° C. By drying to the above, granulated granules were obtained.
(1)タルチレリン水和物2重量部、日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール88重量部及びメタクリル酸コポリマーS(オイドラギットS)10重量部を高速撹拌造粒装置(深江パウテック製、超小型ハイスピードミキサー)に仕込み、1分間予混合した。当該混合物に精製水9.3重量部を添加しながら約3分間造粒後、造粒物を通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。 Example 26
(1) High-speed agitation granulation of 2 parts by weight of talcylerin hydrate, 88 parts by weight of D-mannitol and 10 parts by weight of methacrylic acid copolymer S (Eudragit S) sieved with a Japanese Pharmacopoeia 22 mesh sieve (mesh opening: 710 μm) It was charged in an apparatus (Fukae Pautech, ultra-compact high-speed mixer) and premixed for 1 minute. After granulating for about 3 minutes while adding 9.3 parts by weight of purified water to the mixture, the granulated product was dried at 50 ° C. for 2 hours in a vented box dryer to obtain granulated granules.
(1)アロプリノール35重量部及び日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール62重量部を流動層造粒機(パウレック製、MP-01/03)に仕込み、給気温度60℃で、8%ヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;HF)の80%(W/W)エタノール水溶液39.7重量部を約15分間かけて噴霧しながら造粒後、造粒物の温度が40℃以上になるまで乾燥することにより、造粒顆粒を得た。 Example 27
(1) 35 parts by weight of allopurinol and 62 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (aperture: 710 μm) were charged into a fluidized bed granulator (manufactured by Pauleck, MP-01 / 03). After granulation while spraying 39.7 parts by weight of 80% (W / W) aqueous ethanol solution of 8% hydroxypropylmethylcellulose acetate succinate (grade; HF) at an air temperature of 60 ° C. over about 15 minutes, the granulated product Granules were obtained by drying until the temperature became 40 ° C. or higher.
(1)アバナフィル34.5重量部及び日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール61.9重量部を流動層造粒機(パウレック製、MP-01/03)に仕込み、給気温度50℃で、ヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;HF)3.6重量部を精製水53.1重量部に分散させた液を約25分間かけて噴霧しながら造粒した。造粒物の温度が37℃以上になるまで乾燥することにより、主薬顆粒を得た。 Example 28
(1) A fluidized bed granulator (Powrec, MP-01 / 03) containing 34.5 parts by weight of avanafil and 61.9 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (mesh size: 710 μm) And granulated while spraying a liquid in which 3.6 parts by weight of hydroxypropylmethylcellulose acetate succinate (grade; HF) is dispersed in 53.1 parts by weight of purified water at an air supply temperature of 50 ° C. over about 25 minutes. did. The active ingredient granule was obtained by drying until the temperature of the granulated product reached 37 ° C or higher.
実施例28(1)の主薬顆粒290重量部、実施例28(2)のフマル酸顆粒46重量部、クロスポビドン3.5重量部、アスパルテーム3.5重量部及びステアリン酸マグネシウム7重量部を混合し、打錠用顆粒を得た。当該打錠用顆粒を用い、1錠当たり350mgとなるよう、ロータリー打錠機(菊水製作所製、COLLECT 12HUK、杵:直径10mm、打錠圧:600kg/杵)で圧縮成形することにより、口腔内速崩壊性錠(硬度:52N、口腔内での崩壊時間:25秒)を得た。 Example 29
290 parts by weight of the main drug granules of Example 28 (1), 46 parts by weight of fumaric acid granules of Example 28 (2), 3.5 parts by weight of crospovidone, 3.5 parts by weight of aspartame and 7 parts by weight of magnesium stearate Thus, granules for tableting were obtained. By using the granules for tableting, compression molding is carried out with a rotary tableting machine (manufactured by Kikusui Seisakusho, COLLECT 12HUK, punch: diameter 10 mm, tableting pressure: 600 kg / 杵) by using the granules for tableting. A rapidly disintegrating tablet (hardness: 52 N, disintegration time in the oral cavity: 25 seconds) was obtained.
(1)アバナフィル36.2重量部及び日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール60重量部を流動層造粒機(パウレック製、MP-01/03)に仕込み、給気温度50℃で、ヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;HF)3.8重量部を精製水55.7重量部に分散させた液を約25分間かけて噴霧しながら造粒した。造粒物の温度が37℃以上になるまで乾燥することにより、主薬顆粒を得た。 Example 30
(1) 36.2 parts by weight of avanafil and 60 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (mesh size: 710 μm) were charged into a fluidized bed granulator (MP-01 / 03, manufactured by Paulek). At a supply temperature of 50 ° C., granulation was carried out while spraying a solution in which 3.8 parts by weight of hydroxypropylmethylcellulose acetate succinate (grade; HF) was dispersed in 55.7 parts by weight of purified water over about 25 minutes. The active ingredient granule was obtained by drying until the temperature of the granulated product reached 37 ° C or higher.
(1)塩酸イミダプリル3.1重量部及び日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール90.9重量部を流動層造粒機(パウレック製、MP-01/03)に仕込み、給気温度60℃で、8%ヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;HF)の80%(W/W)エタノール水溶液38.5重量部を約30分間かけて噴霧しながら造粒した。造粒物の温度が40℃以上になるまで乾燥することにより、造粒顆粒を得た。 Example 31
(1) 3.1 parts by weight of imidapril hydrochloride and 90.9 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (mesh size: 710 μm) were added to a fluidized bed granulator (MP-01 / 03, manufactured by Paulec). And granulated while spraying 38.5 parts by weight of 80% (W / W) ethanol solution of 8% hydroxypropylmethylcellulose acetate succinate (grade; HF) at an air supply temperature of 60 ° C. over about 30 minutes did. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
(1)塩酸イミダプリル3.1重量部及び日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール92.9重量部を流動層造粒機(パウレック製、MP-01/03)に仕込み、給気温度50℃で、2.7%ヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;HF)の80%(W/W)エタノール水溶液38.7重量部を約15分間かけて噴霧しながら造粒した。造粒物の温度が40℃以上になるまで乾燥することにより、造粒顆粒を得た。 Example 32
(1) 3.1 parts by weight of imidapril hydrochloride and 92.9 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (mesh size: 710 μm) were added to a fluidized bed granulator (MP-01 / 03, manufactured by Paulec). And spraying 38.7 parts by weight of an aqueous solution of 80% (W / W) ethanol of 2.7% hydroxypropylmethylcellulose acetate succinate (grade; HF) at an air supply temperature of 50 ° C. over about 15 minutes. Granulated. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
(1)塩酸イミダプリル3.1重量部及び日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール90.9重量部を流動層造粒機(パウレック製、MP-01/03)に仕込み、給気温度50℃で、8%エチルセルロースの80%(W/W)エタノール水溶液38.5重量部を約15分間かけて噴霧しながら造粒した。造粒物の温度が40℃以上になるまで乾燥することにより、造粒顆粒を得た。 Example 33
(1) 3.1 parts by weight of imidapril hydrochloride and 90.9 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (mesh size: 710 μm) were added to a fluidized bed granulator (MP-01 / 03, manufactured by Paulec). And granulated while spraying 38.5 parts by weight of 80% (W / W) ethanol aqueous solution of 8% ethyl cellulose over about 15 minutes at an air supply temperature of 50 ° C. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
(1)塩酸イミダプリル3.1重量部及び日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール90.9重量部を流動層造粒機(パウレック製、MP-01/03)に仕込み、給気温度50℃で、8%エチルセルロースの80%(W/W)エタノール水溶液38.7重量部を約15分間かけて噴霧しながら造粒した。造粒物の温度が40℃以上になるまで乾燥することにより、造粒顆粒を得た。 Example 34
(1) 3.1 parts by weight of imidapril hydrochloride and 90.9 parts by weight of D-mannitol sieved with a Japanese Pharmacopoeia 22 mesh sieve (mesh size: 710 μm) were added to a fluidized bed granulator (MP-01 / 03, manufactured by Paulec). And granulated while spraying 38.7 parts by weight of an 80% (W / W) ethanol aqueous solution of 8% ethylcellulose over about 15 minutes at an air supply temperature of 50 ° C. A granulated granule was obtained by drying until the temperature of the granulated product reached 40 ° C or higher.
(1)日本薬局方60メッシュ篩(目開き:250μm)で篩過したソルビトール97重量部及びヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;HF)3重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加しながら造粒後、造粒物を通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。
(2)上記(1)の造粒顆粒283.5重量部、クロスポビドン15重量部及びステアリン酸マグネシウム1.5重量部を混合し、打錠用顆粒を調製した。該打錠用顆粒を用い、1錠当たり300mgとなるよう、コンパクションアナライザー(菊水製作所製、杵:直径10mm、打錠圧:200kg/杵)で圧縮成形することにより、錠剤を得た(硬度:57N、口腔内での崩壊時間:129秒)。 Comparative Example 1
(1) 5 parts by weight of 80% (W / W) in a mixture of 97 parts by weight of sorbitol and 3 parts by weight of hydroxypropylmethylcellulose acetate succinate (grade; HF) sieved with a 60-mesh screen (mesh size: 250 μm) W) After granulation while adding an aqueous ethanol solution, the granulated product was dried at 50 ° C. for 2 hours in a vented box dryer to obtain granulated granules.
(2) 283.5 parts by weight of the granulated granules (1), 15 parts by weight of crospovidone and 1.5 parts by weight of magnesium stearate were mixed to prepare granules for tableting. Using the granules for tableting, tablets were obtained by compression molding with a compaction analyzer (manufactured by Kikusui Seisakusho, 杵: diameter 10 mm, tableting pressure: 200 kg / 杵) to give 300 mg per tablet (hardness: 57N, disintegration time in the oral cavity: 129 seconds).
(1)メノウ乳鉢で粉砕後、日本薬局方60メッシュ篩(目開き:250μm)で篩過した精製白糖97重量部、ヒドロキシプロピルメチルセルロースアセテートサクシネート(グレード;HF)3重量部の重量比の混合末に5重量部の80%(W/W)エタノール水溶液を添加して造粒後、通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。
(2)上記(1)の造粒顆粒283.5重量部、クロスポビドン15重量部及びステアリン酸マグネシウム1.5重量部を混合し、打錠用顆粒を調製した。当該打錠用顆粒を用い、1錠当たり300mgとなるよう、コンパクションアナライザー(菊水製作所製、杵:直径10mm、打錠圧:950kg/杵)で圧縮成形することにより、錠剤を得た(硬度:53N、口腔内での崩壊時間:65秒)。 Comparative Example 2
(1) Mixing in a weight ratio of 97 parts by weight of refined white sugar and 3 parts by weight of hydroxypropylmethylcellulose acetate succinate (grade; HF), which was pulverized in an agate mortar and then passed through a 60-mesh pharmacopoeia (mesh size: 250 μm). Finally, 5 parts by weight of 80% (W / W) ethanol aqueous solution was added and granulated, and then dried at 50 ° C. for 2 hours in a vented box dryer to obtain granulated granules.
(2) 283.5 parts by weight of the granulated granules (1), 15 parts by weight of crospovidone and 1.5 parts by weight of magnesium stearate were mixed to prepare granules for tableting. Using the granules for tableting, tablets were obtained by compression molding with a compaction analyzer (manufactured by Kikusui Seisakusho, Kashiwa: diameter 10 mm, tableting pressure: 950 kg / kg) (tablet: hardness: 53N, disintegration time in the oral cavity: 65 seconds).
(1)日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール97重量部、ヒドロキシプロピルメチルセルロース(グレード;TC-5EW)3重量部の重量比の混合末に5重量部の80%(W/W)エタノール水溶液を添加しながら造粒後、造粒物を通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。
(2)上記(1)の造粒顆粒283.5重量部、クロスポビドン15重量部及びステアリン酸マグネシウム1.5重量部を混合し、打錠用顆粒を調製した。当該打錠用顆粒を用い、1錠当たり300mgとなるよう、コンパクションアナライザー(菊水製作所製、杵:直径10mm、打錠圧:900kg/杵)で圧縮成形することにより、錠剤を得た(硬度:52N、口腔内での崩壊時間:105秒)。 Comparative Example 3
(1) 5 parts by weight in a mixed powder having a weight ratio of 97 parts by weight of D-mannitol and 3 parts by weight of hydroxypropylmethylcellulose (grade: TC-5EW) sieved with a 22-mesh screen (mesh size: 710 μm) After granulation while adding an 80% (W / W) aqueous ethanol solution, the granulated product was dried at 50 ° C. for 2 hours in a vented box dryer to obtain granulated granules.
(2) 283.5 parts by weight of the granulated granules (1), 15 parts by weight of crospovidone and 1.5 parts by weight of magnesium stearate were mixed to prepare granules for tableting. Using the granules for tableting, tablets were obtained by compression molding with a compaction analyzer (manufactured by Kikusui Seisakusho, cocoon: diameter 10 mm, tableting pressure: 900 kg / 杵) to give 300 mg per tablet (hardness: 52N, disintegration time in the oral cavity: 105 seconds).
(1)日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール97重量部,ヒドロキシプロピルセルロース(グレード;HPC-SL)3重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加しながら造粒後、通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。
(2)上記(1)の造粒顆粒283.5重量部,クロスポビドン15重量部及びステアリン酸マグネシウム1.5重量部を混合し、打錠用顆粒を調製した。当該打錠用顆粒を用い、1錠当たり300mgとなるよう、コンパクションアナライザー(菊水製作所製、杵:直径10mm、打錠圧:850kg/杵)で圧縮成形することにより、錠剤を得た(硬度:52N、口腔内での崩壊時間:37秒)。 Comparative Example 4
(1) 5% by weight of 80% (W) in a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of hydroxypropylcellulose (grade: HPC-SL) sieved with a 22-mesh sieve (mesh size: 710 μm) / W) After granulation while adding an aqueous ethanol solution, granulation granules were obtained by drying at 50 ° C. for 2 hours in a vented box dryer.
(2) 283.5 parts by weight of the granulated granules of (1), 15 parts by weight of crospovidone and 1.5 parts by weight of magnesium stearate were mixed to prepare granules for tableting. Tablets were obtained by using the granules for tableting by compression molding with a compaction analyzer (manufactured by Kikusui Seisakusho, cocoon: diameter 10 mm, tableting pressure: 850 kg / よ う) so as to be 300 mg per tablet (hardness: 52N, disintegration time in the oral cavity: 37 seconds).
(1)日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール97重量部、トウモロコシデンプン3重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加しながら造粒後、通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。
(2)上記(1)の造粒顆粒283.5重量部、クロスポビドン15重量部及びステアリン酸マグネシウム1.5重量部を混合し、打錠用顆粒を調製した。当該打錠用顆粒を用い、1錠当たり300mgとなるよう、コンパクションアナライザー(菊水製作所製、杵:直径10mm、打錠圧:2000kg/杵)で圧縮成形することにより、錠剤を得た(硬度:57N、口腔内での崩壊時間:15秒)。一方、打錠圧を2000kg/杵まであげても、錠剤硬度が80N以上の錠剤は調製できなかった。 Comparative Example 5
(1) 5 parts by weight of 80% (W / W) ethanol aqueous solution was added to a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of corn starch sieved with a Japanese pharmacopoeia 22 mesh sieve (aperture: 710 μm). Then, after granulation, granulated granules were obtained by drying at 50 ° C. for 2 hours in a ventilated box dryer.
(2) 283.5 parts by weight of the granulated granules (1), 15 parts by weight of crospovidone and 1.5 parts by weight of magnesium stearate were mixed to prepare granules for tableting. Tablets were obtained by using the granules for tableting and compression-molding with a compaction analyzer (manufactured by Kikusui Seisakusho, cocoon: diameter 10 mm, tableting pressure: 2000 kg / 杵) to give 300 mg per tablet (hardness: 57N, disintegration time in the oral cavity: 15 seconds). On the other hand, even when the tableting pressure was increased to 2000 kg / kg, tablets having a tablet hardness of 80 N or more could not be prepared.
(1)日本薬局方22メッシュ篩(目開き:710μm)で篩過したD-マンニトール97重量部、クロスポビドン3重量部の混合物に5重量部の80%(W/W)エタノール水溶液を添加しながら造粒後、造粒物を通気式箱型乾燥機中50℃で2時間乾燥することにより、造粒顆粒を得た。
(2)上記(1)の造粒顆粒283.5重量部、クロスポビドン15重量部及びステアリン酸マグネシウム1.5重量部を混合し、打錠用顆粒を調製した。当該打錠用顆粒を用い、1錠当たり300mgとなるよう、コンパクションアナライザー(菊水製作所製、杵:直径10mm、打錠圧:1500kg/杵)で圧縮成形することにより、錠剤を得た(硬度:52N、口腔内での崩壊時間:15秒)。一方、打錠圧を2000kg/杵まであげても、錠剤硬度が80N以上の錠剤は得られなかった。 Comparative Example 6
(1) 5 parts by weight of 80% (W / W) ethanol aqueous solution was added to a mixture of 97 parts by weight of D-mannitol and 3 parts by weight of crospovidone sieved with a 22-mesh pharmacopoeia (mesh size: 710 μm). After granulation, the granulated product was dried at 50 ° C. for 2 hours in a vented box dryer to obtain granulated granules.
(2) 283.5 parts by weight of the granulated granules (1), 15 parts by weight of crospovidone and 1.5 parts by weight of magnesium stearate were mixed to prepare granules for tableting. Using the granules for tableting, tablets were obtained by compression molding with a compaction analyzer (manufactured by Kikusui Seisakusho, cocoon: diameter 10 mm, tableting pressure: 1500 kg / 杵) so as to be 300 mg per tablet (hardness: 52N, disintegration time in the oral cavity: 15 seconds). On the other hand, even when the tableting pressure was increased to 2000 kg / kg, tablets with a tablet hardness of 80 N or more were not obtained.
Claims (32)
- (a)活性成分;(b)水への濡れ性が良好な賦形剤;(c)成形性が良好で、前記賦形剤の水への濡れ性を実質的に低下させない水不溶性高分子;及び(d)崩壊剤からなる混合物を圧縮成形して得られる口腔内での崩壊時間が60秒以内である口腔内速崩壊性錠。 (A) active ingredient; (b) excipient with good wettability to water; (c) water-insoluble polymer with good moldability and which does not substantially reduce the wettability of the excipient to water. And (d) an intraoral rapidly disintegrating tablet obtained by compression molding a mixture comprising a disintegrant and having an oral disintegration time of 60 seconds or less.
- 水への濡れ性が良好な賦形剤がマンニトール、エリスリトール及びキシリトールからなる群から選ばれる1種以上の糖アルコールであり、成形性が良好で前記賦形剤の水への濡れ性を実質的に低下させない水不溶性高分子がヒドロキシプロピルメチルセルロースアセテートサクシネート、エチルセルロース、ヒドロキシプロピルメチルセルロースフタレート、カルボキシメチルエチルセルロース、メタクリル酸コポリマーL、メタクリル酸コポリマーS及びアミノメタクリレートコポリマーからなる群から選ばれる1種以上の水不溶性高分子である、請求項1記載の口腔内速崩壊性錠。 The excipient having good water wettability is one or more sugar alcohols selected from the group consisting of mannitol, erythritol and xylitol, and has good moldability and substantially improves the wettability of the excipient to water. At least one water selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, ethylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer S and aminomethacrylate copolymer. The intraorally rapidly disintegrating tablet according to claim 1, which is an insoluble polymer.
- 錠剤100重量部に対し、水への濡れ性が良好な賦形剤の配合量が30~95重量部、成形性が良好で前記賦形剤の水への濡れ性を実質的に低下させない水不溶性高分子の配合量が1~10重量部、かつ崩壊剤の配合量が1~15重量部である請求項1又は2記載の口腔内速崩壊性錠。 30 to 95 parts by weight of an excipient having good wettability with water with respect to 100 parts by weight of the tablet, water that does not substantially reduce the wettability of the excipient with good moldability The intraorally rapidly disintegrating tablet according to claim 1 or 2, wherein the amount of the insoluble polymer is 1 to 10 parts by weight and the amount of the disintegrant is 1 to 15 parts by weight.
- 錠剤強度が100~300N/cm2である、請求項3記載の口腔内速崩壊性錠。 The intraoral rapidly disintegrating tablet according to claim 3, wherein the tablet strength is 100 to 300 N / cm 2 .
- 錠剤強度が110~300N/cm2である、請求項3記載の口腔内速崩壊性錠。 The intraoral rapidly disintegrating tablet according to claim 3, wherein the tablet strength is 110 to 300 N / cm 2 .
- 錠剤強度が120~300N/cm2である、請求項3記載の口腔内速崩壊性錠。 The intraoral rapidly disintegrating tablet according to claim 3, wherein the tablet strength is 120 to 300 N / cm 2 .
- 口腔内での崩壊時間が5~45秒である、請求項4、5又は6記載の口腔内速崩壊性錠。 The intraoral quick disintegrating tablet according to claim 4, 5 or 6, wherein the disintegration time in the oral cavity is 5 to 45 seconds.
- 口腔内での崩壊時間が5~30秒である、請求項4、5又は6記載の口腔内速崩壊性錠。 The intraoral quick disintegrating tablet according to claim 4, 5 or 6, wherein the disintegration time in the oral cavity is 5 to 30 seconds.
- 口腔内での崩壊時間が5~20秒である、請求項4、5又は6記載の口腔内速崩壊性錠。 The intraoral fast disintegrating tablet according to claim 4, 5 or 6, wherein the disintegration time in the oral cavity is 5 to 20 seconds.
- 硬度と錠剤重量との比の値が0.2N/mg以上である、請求項4、5又は6記載の口腔内速崩壊性錠。 7. The intraoral quick disintegrating tablet according to claim 4, 5 or 6, wherein the ratio of hardness to tablet weight is 0.2 N / mg or more.
- 硬度と錠剤重量との比の値が0.3N/mg以上である、請求項4、5又は6記載の口腔内速崩壊性錠。 The intraoral quick disintegrating tablet according to claim 4, 5 or 6, wherein the value of the ratio of hardness to tablet weight is 0.3 N / mg or more.
- 活性成分がニセルゴリン、塩酸イミダプリル、フマル酸ビソプロロール、タルチレリン水和物、アロプリノール又はアバナフィルである、請求項4、5又は6記載の口腔内速崩壊性錠。 The intraoral quick disintegrating tablet according to claim 4, 5 or 6, wherein the active ingredient is nicergoline, imidapril hydrochloride, bisoprolol fumarate, tartyrelin hydrate, allopurinol or avanafil.
- 活性成分がニセルゴリン、塩酸イミダプリル、フマル酸ビソプロロール又はタルチレリン水和物であり、活性成分の配合量が、錠剤100重量部に対して0.1~70重量部である、請求項12記載の口腔内速崩壊性錠。 The oral cavity according to claim 12, wherein the active ingredient is nicergoline, imidapril hydrochloride, bisoprolol fumarate or taltileline hydrate, and the amount of the active ingredient is 0.1 to 70 parts by weight with respect to 100 parts by weight of the tablet. Fast disintegrating tablet.
- 活性成分がニセルゴリン、塩酸イミダプリル、フマル酸ビソプロロール又はタルチレリン水和物であり、活性成分の配合量が、錠剤100重量部に対して0.5~20重量部である、請求項12記載の口腔内速崩壊性錠。 The oral cavity according to claim 12, wherein the active ingredient is nicergoline, imidapril hydrochloride, bisoprolol fumarate or taltileline hydrate, and the amount of the active ingredient is 0.5 to 20 parts by weight with respect to 100 parts by weight of the tablet. Fast disintegrating tablet.
- 活性成分がニセルゴリン、塩酸イミダプリル、フマル酸ビソプロロール又はタルチレリン水和物であり、活性成分の配合量が、錠剤100重量部に対して1~15重量部である、請求項12記載の口腔内速崩壊性錠。 13. The intraoral rapid disintegration according to claim 12, wherein the active ingredient is nicergoline, imidapril hydrochloride, bisoprolol fumarate or taltileline hydrate, and the amount of the active ingredient is 1 to 15 parts by weight with respect to 100 parts by weight of the tablet. Sex tablets.
- 活性成分がニセルゴリン、塩酸イミダプリル、フマル酸ビソプロロール又はタルチレリン水和物であり、活性成分の配合量が、錠剤100重量部に対して1~10重量部である、請求項12記載の口腔内速崩壊性錠。 13. The intraoral rapid disintegration according to claim 12, wherein the active ingredient is nicergoline, imidapril hydrochloride, bisoprolol fumarate or taltileline hydrate, and the amount of the active ingredient is 1 to 10 parts by weight with respect to 100 parts by weight of the tablet. Sex tablets.
- 活性成分がアロプリノール又はアバナフィルであり、活性成分の配合量が、錠剤100重量部に対して10~50重量部である、請求項12記載の口腔内速崩壊性錠。 The orally rapidly disintegrating tablet according to claim 12, wherein the active ingredient is allopurinol or avanafil, and the amount of the active ingredient is 10 to 50 parts by weight with respect to 100 parts by weight of the tablet.
- (a)ニセルゴリン、塩酸イミダプリル、フマル酸ビソプロロール、タルチレリン水和物、アロプリノール及びアバナフィルからなる群から選ばれる活性成分;(b)マンニトール、エリスリトール及びキシリトールからなる群から選ばれる1種以上の賦形剤;(c)ヒドロキシプロピルメチルセルロースアセテートサクシネート、エチルセルロース、ヒドロキシプロピルメチルセルロースフタレート、カルボキシメチルエチルセルロース、メタクリル酸コポリマーL、メタクリル酸コポリマーS及びアミノメタクリレートコポリマーからなる群から選ばれる1種以上の水不溶性高分子;(d)カルボキシメチルセルロースカルシウム、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロース、架橋カルボキシメチルセルロースナトリウム、結晶セルロース、トウモロコシデンプン、部分アルファー化デンプン、カルボキシメチルスターチナトリウム及び架橋ポリビニルピロリドンからなる群から選ばれる1種以上の崩壊剤;及び(e)滑沢剤の混合物(当該混合物は結合剤、可塑剤、コーティング剤、凝集防止剤、可溶化剤、甘味料、酸味料、矯味剤、pH調整剤、溶解補助剤、着色料及び香料からなる群から選ばれる1種以上の添加物を含有していてもよい)を圧縮成形して得られる口腔内での崩壊時間が60秒以内である口腔内速崩壊性錠。 (A) an active ingredient selected from the group consisting of nicergoline, imidapril hydrochloride, bisoprolol fumarate, tartyrelin hydrate, allopurinol and avanafil; (b) one or more excipients selected from the group consisting of mannitol, erythritol and xylitol (C) one or more water-insoluble polymers selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, ethylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer S and aminomethacrylate copolymer; (D) carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, carboxymethylcellulose, crosslinked carboxymethylcellulose One or more disintegrants selected from the group consisting of sodium, crystalline cellulose, corn starch, partially pregelatinized starch, sodium carboxymethyl starch and crosslinked polyvinylpyrrolidone; and (e) a mixture of lubricants (the mixture is a binder) Contains one or more additives selected from the group consisting of a plasticizer, a coating agent, an anti-aggregation agent, a solubilizer, a sweetener, an acidulant, a corrigent, a pH adjuster, a solubilizer, a colorant and a fragrance. Orally disintegrating tablets obtained by compression molding of the oral disintegration time within 60 seconds.
- 錠剤100重量部に対し、賦形剤の配合量が30~95重量部、水不溶性高分子の配合量が1~10重量部、崩壊剤の配合量が1~15重量部、滑沢剤の配合量が0.01~3重量部である、請求項18記載の口腔内速崩壊性錠。 30 to 95 parts by weight of excipient, 1 to 10 parts by weight of water-insoluble polymer, 1 to 15 parts by weight of disintegrant, The intraorally rapidly disintegrating tablet according to claim 18, wherein the amount is 0.01 to 3 parts by weight.
- 錠剤強度が100~300N/cm2である、請求項19記載の口腔内速崩壊性錠。 The intraorally rapidly disintegrating tablet according to claim 19, wherein the tablet strength is 100 to 300 N / cm 2 .
- 錠剤強度が110~300N/cm2である、請求項19記載の口腔内速崩壊性錠。 The orally rapidly disintegrating tablet according to claim 19, wherein the tablet strength is 110 to 300 N / cm 2 .
- 錠剤強度が120~300N/cm2である、請求項19記載の口腔内速崩壊性錠。 The intraorally rapidly disintegrating tablet according to claim 19, wherein the tablet strength is 120 to 300 N / cm 2 .
- 口腔内での崩壊時間が5~45秒である、請求項20、21又は22記載の口腔内速崩壊性錠。 The intraoral quick disintegrating tablet according to claim 20, 21 or 22, wherein the disintegration time in the oral cavity is 5 to 45 seconds.
- 口腔内での崩壊時間が5~30秒である、請求項20、21又は22記載の口腔内速崩壊性錠。 The intraoral quick disintegrating tablet according to claim 20, 21 or 22, wherein the disintegration time in the oral cavity is 5 to 30 seconds.
- 口腔内での崩壊時間が5~20秒である、請求項20、21又は22記載の口腔内速崩壊性錠。 The intraoral quick disintegrating tablet according to claim 20, 21 or 22, wherein the disintegration time in the oral cavity is 5 to 20 seconds.
- 硬度と錠剤重量との比の値が0.2N/mg以上である、請求項20、21又は22記載の口腔内速崩壊性錠。 The intraoral rapidly disintegrating tablet according to claim 20, 21 or 22, wherein the value of the ratio of hardness to tablet weight is 0.2 N / mg or more.
- 硬度と錠剤重量との比の値が0.3N/mg以上である、請求項20、21又は22記載の口腔内速崩壊性錠。 The intraoral quick disintegrating tablet according to claim 20, 21 or 22, wherein the value of the ratio of hardness to tablet weight is 0.3 N / mg or more.
- 賦形剤がマンニトール、水不溶性高分子がヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート又はカルボキシメチルエチルセルロースである、請求項20、21又は22記載の口腔内速崩壊性錠。 The rapidly disintegrating buccal tablet according to claim 20, 21 or 22, wherein the excipient is mannitol and the water-insoluble polymer is hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate or carboxymethylethylcellulose.
- i)(a)活性成分;(b)水への濡れ性が良好な賦形剤;(c)成形性が良好で、前記賦形剤の水への濡れ性を実質的に低下させない水不溶性高分子;及び(d)崩壊剤の混合物(当該混合物は滑沢剤、結合剤、可塑剤、コーティング剤、凝集防止剤、可溶化剤、甘味料、酸味料、矯味剤、pH調整剤、溶解補助剤、着色料及び香料からなる群から選ばれる1種以上の添加物を含有していてもよい)を調製し、次いでii)上記i)で得られた混合物を圧縮成形することからなる、口腔内での崩壊時間が60秒以内である口腔内速崩壊性錠の製造方法。 i) (a) active ingredient; (b) excipient with good wettability in water; (c) water insolubility that has good moldability and does not substantially reduce the wettability of the excipient in water. Polymer; and (d) a mixture of disintegrants (the mixture is a lubricant, binder, plasticizer, coating agent, anti-aggregation agent, solubilizer, sweetener, acidulant, corrigent, pH adjuster, dissolution) Comprising at least one additive selected from the group consisting of adjuvants, colorants and fragrances), and then ii) compressing the mixture obtained in i) above, A method for producing an orally rapidly disintegrating tablet, wherein the disintegration time in the oral cavity is within 60 seconds.
- 活性成分がニセルゴリン、塩酸イミダプリル、フマル酸ビソプロロール、タルチレリン水和物、アロプリノール又はアバナフィルであり、水への濡れ性が良好な賦形剤がマンニトール、エリスリトール又はキシリトールであり、成形性が良好で前記賦形剤の水への濡れ性を実質的に低下させない水不溶性高分子がヒドロキシプロピルメチルセルロースアセテートサクシネート、エチルセルロース、ヒドロキシプロピルメチルセルロースフタレート、カルボキシメチルエチルセルロース、メタクリル酸コポリマーL、メタクリル酸コポリマーS及びアミノメタクリレートコポリマーからなる群から選ばれる1種以上の水不溶性高分子であり、崩壊剤がカルボキシメチルセルロースカルシウム、カルボキシメチルセルロース、架橋カルボキシメチルセルロースナトリウム、カルボキシメチルスターチナトリウム又は架橋ポリビニルピロリドンである、請求項29記載の製造方法。 The active ingredient is nicergoline, imidapril hydrochloride, bisoprolol fumarate, tartyrelin hydrate, allopurinol or avanafil, and the excipient with good wettability to water is mannitol, erythritol or xylitol, the moldability is good, and Water insoluble polymers that do not substantially reduce the wettability of the dosage form in water are hydroxypropylmethylcellulose acetate succinate, ethylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer S and amino methacrylate copolymer One or more water-insoluble polymers selected from the group consisting of: carboxymethylcellulose calcium, carboxymethylcellulose, crosslinked carboxymethyl Le cellulose sodium, carboxymethyl starch sodium or crosslinked polyvinylpyrrolidone, a manufacturing method of claim 29, wherein.
- 口腔内速崩壊性錠の錠剤強度が100~300N/cm2である、請求項30記載の製造方法。 The production method according to claim 30, wherein the tablet strength of the orally rapidly disintegrating tablet is 100 to 300 N / cm 2 .
- 直径が5~10mm、重量が100~300mg、かつ硬度が15N~90Nである、請求項1又は18記載の口腔内速崩壊性錠。 The intraorally rapidly disintegrating tablet according to claim 1 or 18, which has a diameter of 5 to 10 mm, a weight of 100 to 300 mg, and a hardness of 15 N to 90 N.
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2009
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- 2009-11-25 CN CN200980147342.3A patent/CN102223880B/en active Active
- 2009-11-25 JP JP2010540492A patent/JP5227424B2/en active Active
- 2009-11-25 CN CN201410145488.7A patent/CN103919742B/en active Active
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- 2009-11-25 KR KR1020117011761A patent/KR101753411B1/en active IP Right Grant
- 2009-11-25 WO PCT/JP2009/069850 patent/WO2010061846A1/en active Application Filing
- 2009-11-25 EP EP20090829094 patent/EP2368544A4/en not_active Withdrawn
- 2009-11-25 US US13/130,819 patent/US20110229570A1/en not_active Abandoned
- 2009-11-25 EP EP14178298.7A patent/EP2808013A1/en not_active Withdrawn
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- 2013-01-31 JP JP2013017294A patent/JP5560353B2/en active Active
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Also Published As
Publication number | Publication date |
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JP2014196360A (en) | 2014-10-16 |
CN103919742B (en) | 2017-04-12 |
JP2013100344A (en) | 2013-05-23 |
JP5722953B2 (en) | 2015-05-27 |
CN103919742A (en) | 2014-07-16 |
CN102223880B (en) | 2017-04-26 |
KR20140096178A (en) | 2014-08-04 |
KR20110089410A (en) | 2011-08-08 |
EP2368544A1 (en) | 2011-09-28 |
JP2013213038A (en) | 2013-10-17 |
CN102988318A (en) | 2013-03-27 |
US20110229570A1 (en) | 2011-09-22 |
KR101753411B1 (en) | 2017-07-03 |
EP2368544A4 (en) | 2012-08-15 |
JPWO2010061846A1 (en) | 2012-04-26 |
CN102223880A (en) | 2011-10-19 |
KR101704156B1 (en) | 2017-02-07 |
JP5560353B2 (en) | 2014-07-23 |
JP5227424B2 (en) | 2013-07-03 |
EP2808013A1 (en) | 2014-12-03 |
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